Later, it served as a wagon trail to link cinnabar mines on Mount St. Helena to San Pablo Bay, the northern portion of the San Francisco Bay,[1] and was the first permanent road from Napa to Calistoga.

[2] Silver was discovered in Napa Valley in 1858, and wine production began in the 1870s, making the road an important trade route.

Charles Bolles, a highway bandit also known as "Black Bart", preyed on the road's travelers in the 1880s.

A Phylloxera plague and Prohibition forced most but not all of the local wineries out of business.

[2] Each year in March, the route also plays host to the annual Napa Valley Marathon.