This chapter presents a brief history of the uses of lettuce (Lactuca sativa L.) and its wild North American relatives and reviews the agricultural importance of lettuce and challenges in its cultivation, in relation to nutritional quality, diseases, pests, and edaphic and climatic limitations. The evolution and taxonomy of the genus Lactuca are presented, with a primary focus on the wild Lactuca species of North America, their characterization, biogeography and distribution, habitat ecology, and genepools. Specific examples of phenotypic variability, genetic diversity, and disease resistance of wild Lactuca taxa from both published reports and recent evaluations conducted in our laboratory are also presented. The past (and future) exploitation of wild Lactuca relatives in lettuce breeding is examined and discussed in the broader context of crop improvement. The current status of in situ and ex situ conservation of wild and weedy North American Lactuca is reviewed, along with recommendations on how these genetic resources could be better conserved and utilized.