Deleterious effects of climate change and human activities, as well as diverse environmental stresses, present critical challenges to food production and the maintenance of natural diversity. These challenges may be met by the development of novel crop varieties with increased biotic or abiotic resistance that enables them to thrive in marginal lands. However, considering the diverse interactions between crops and environmental factors, it is surprising that evolutionary principles have been underexploited in addressing these food and environmental challenges. Compared with domesticated cultivars, crop wild relatives (CWRs) have been challenged in natural environments for thousands of years and maintain a much higher level of genetic diversity. In this review, we highlight the significance of CWRs for crop improvement by providing examples of CWRs that have been used to increase biotic and abiotic stress resistance/tolerance and overall yield in various crop species. We also discuss the surge of advanced biotechnologies, such as next-generation sequencing technologies and omics, with particular emphasis on how they have facilitated gene discovery in CWRs. We end the review by discussing the available resources and conservation of CWRs, including the urgent need for CWR prioritization and collection to ensure continuous crop improvement for food sustainability.