The use of wild species is extensive in both high- and low-income countries. At least 50,000 wild species are used by billions of people around the world for food, energy, medicine, material, education or recreation, contributing significantly to efforts to achieve the United Nations Sustainable Development Goals. However, overexploitation remains a major threat to many wild species. Ensuring and enhancing the sustainability of use of wild species is thus essential for human well-being and biodiversity conservation. Globally, the use of wild species is increasing due to growing human demand and efficiency, but its sustainability varies and depends on the social-ecological contexts in which the use occurs. Multiple environmental and social (including economic) drivers affect the sustainability of use of wild species, posing major current and future challenges. In particular, climate change has already increased the vulnerability of many uses and is expected to increase it further in the coming decades, while global and illegal trades are, in many cases, key drivers of unsustainability. There is no single “silver bullet” policy to address these and other major challenges in the sustainable use of wild species. Rather, effective policies need to integrate inclusive actions at multiple scales that adopt right-based approaches, pay attention to equitable distribution of access and costs and benefits, employ participatory processes, strengthen monitoring programs, build robust customary or government institutions and support context-specific policies, as well as adaptive management.