San Ysidro is home to the world's busiest land border crossing, where U.S. Interstate 5 crosses into Mexico at Tijuana. Each year over 14 million vehicles and 40 million people enter the U.S. at the San Ysidro port of entry.

The great majority of these are workers (both of Mexican and U.S. nationality) commuting from Tijuana to jobs in the greater San Diego area and throughout southern California. There is also a thriving reverse traffic, both of workers traveling to maquiladoras in Mexico and those purchasing services (vehicle repairs, hair and beauty services, childcare, medical and dental) or seeking entertainment in Tijuana.

Crossing times are notoriously slow at San Ysidro, particularly for those entering the U.S. in cars. For this reason many cross on foot, which is frequently much faster than the vehicle lane. Some pedestrian travelers own a car in each country, and store them in one of the large parking lots located near the border post, or use the respective public transportation systems of both cities (both systems have a bus station built solely to serve the border crossing point).

Many people frequently visit the fence that separates the beaches at the international border (known as Playas de Tijuana in Mexico, and the Border Field State Beach in the United States).