Vasquez became one of the major shippers of goods between St. Louis and New Orleans. He was also considered one of St. Louis’ "merchant elite." When the first Catholic church was built in St Louis, Vasquez helped finance it and was one of the leading members of its congregation. In 1780, he was appointed lieutenant of the militia formed in anticipation of a British attack on the village. The British and their Native American allies did attack, on May 25-26, 1780, but the garrison and its cannon drove them off.

Vasquez decided to ally himself with Jacques Clamorgan and other merchants in the ill-fated Missouri Company of the 1790s. Formed to bring order and greater profits to the fur trading business, the Missouri Company was plagued by a lack of furs, competition form the British, and attacks by Native American tribes. Virtually all of its partners lost their investments, plunging many of them into financial ruin.