South American years
Lick found his time in Buenos Aires to be difficult, due to his ignorance of Spanish and the turbulent political situation in the country. However, his business thrived and in 1825 Lick left Argentina to tour Europe for a year. On his return trip, his ship was captured by the Portuguese, and the passengers and crew were taken to Montevideo as prisoners of war. Lick escaped captivity and returned to Buenos Aires on foot.

In 1832, Lick decided to return to Stumpstown. He failed to reunite with Barbara Snavely and their son and returned to Buenos Aires. He decided the political situation was too unstable and moved to Valparaíso, Chile. After four years, he again moved his business, this time to Lima, Peru.

In 1846, Lick decided to return to North America and, anticipating the Mexican-American War and the future annexation of California, he decided to settle there. However, a backlog of orders for his pianos delayed him an additional 18 months, as the Mexican workers he employed left to return to their homes and join the Mexican Army following the outbreak of war in April of that year; he finished the orders himself.

California years
Lick arrived in San Francisco, California, in January 1848, bringing with him his tools, work bench, $30,000 in gold, and 600 pounds (300 kg) of chocolate. The chocolate quickly sold, and Lick convinced his neighbor in Peru, the confectioner Domingo Ghirardelli, to move to San Francisco, where he founded the Ghirardelli Chocolate Company.

Upon his arrival, Lick began buying real estate in the small village of San Francisco. The discovery of gold at Sutter's Mill near Sacramento a few days after Lick's arrival in the future state began the California gold rush and created a housing boom in San Francisco, which grew from about one thousand residents in 1848 to over twenty thousand by 1850.

Lick himself got a touch of "gold fever" and went out to mine the metal, but after a week he decided his fortune was to be made by owning land, not digging in it. Lick continued buying land in San Francisco, and also began buying farmland in and around San Jose, where he planted orchards and built the largest flour mill in the state to feed the growing population in San Francisco.

In 1861, Lick began construction of a hotel, which became known as Lick House, at the intersection of Mongomery and Sutter Streets in San Francisco. The hotel had a dining room that could seat 400, based on a similar room at the palace of Versailles. Lick House was considered the finest hotel west of the Mississippi River. The hotel was destroyed in the fire following the San Francisco earthquake of 1906.

Following the construction, Lick returned to his San Jose orchards. In 1874, Lick suffered a massive stroke in the kitchen of his home in Santa Clara. The following morning, he was found by his employee, Thomas Fraser, and taken to Lick House, where he could be better cared for. At the time of his illness, his estates, outside his considerable area in Santa Clara County and San Francisco, included large holdings around Lake Tahoe, a large ranch in Los Angeles County, and all of Santa Catalina Island. James Lick was the richest man in California.

In the next three years, Lick spent his time determining how to dispense with his fortune. He originally wanted to build giant statues of himself and his parents, and erect a pyramid larger than the Great Pyramid of Giza in his own honor in Downtown San Francisco. However, through the efforts of George Davidson, President of the California Academy of the Sciences, Lick was persuaded to leave the greatest portion of his fortune to the establishment of a mountain top observatory, with the largest, most powerful telescope yet built by man.

Lick had had an interest in astronomy since at least 1860, when he and George Madeira, the founder of the first observatory in California, spent several nights observing. They had also met again in 1873 and Lick said the Madeira's telescopes were the only ones he had ever used. In 1875, Thomas Fraser recommended a site at the summit of Mount Hamilton, near San Jose. Lick approved, on the condition that Santa Clara County build a "first class" road to the site. The county agreed and the hand built road was completed by the fall of 1876.

On October 1, 1876, Lick died in his room in Lick House, San Francisco. In 1887, his body was moved to its final resting place, under the future home of the Great Lick Refracting Telescope.

Lick's legacy
1. Lick's will stipulated that all of his fortune should be used for the public good, including $700,000 for the building of the observatory.
2. In 1888, Lick Observatory was completed and given to the University of California as the Lick Astronomical Department. The Observatory was the first permanently staffed mountain top observatory in the world and housed the largest refracting telescope in the world at that time.
3. In 1887 Lick's body was buried under the future site of the telescope, with a brass tablet bearing the inscription, "Here lies the body of James Lick."
4. James Lick Mansion in Santa Clara is a nationally registered historical landmark, and is leased at very low rates to non-profit organizations. As of 2003 the mansion is occupied by the S.A.F.E. Place.
5. In 1884, the Lick Old Ladies Home in San Francisco was established with a grant from the Lick estate.
6. The Conservatory of Flowers and the statue of Francis Scott Key in Golden Gate Park were donated to San Francisco by Lick.
7. The Pioneer Monument in front of San Francisco's City Hall was donated by Lick to the city.
8. James Lick High School in San Jose and James Lick Middle School, Lick-Wilmerding High School, and the U.S. Route 101, all in San Francisco, are named in his honor.
9. The Lick crater on the Moon and the asteroid 1951 Lick are named after him.
10. Lickdale, Pennsylvania, a village approximately 3 miles west of Fredericksburg, Pennsylvania (formerly Stumpstown), was named for James Lick. Lickdale was a prominent 19th century canal port along a branch of the Union Canal and contained a large commercial ice house.