In the mid-twentieth century, the Seris (Comcaac), a small mobile hunter-gatherer and fishing people of northwestern Mexico, became almost entirely sedentary. They had for centuries survived in the isolated desert and coast along the eastern central Gulf of California, an area of rich biodiversity. The move to permanent settlements facilitated access to non-traditional foods that began to markedly impact their traditional diet of desert and marine resources, including mollusks. Although fish and sea turtles continued to be an important part of that diet, consumption of mollusks declined significantly, accompanied by a gradual loss of knowledge of their names and related ecological information, a loss evident among younger Seris today. This paper explores the role of mollusks in the Seri culture and associated changes that have taken place over the past century. Published accounts, oral tradition, historical records, and current investigation describe how the Seris adopted a sedentary lifestyle, and the impact that the change has had on their traditional diet, ecological knowledge, subsistence practices, and health.