Living marine resources have strong links with human health and well-being that are complex, still not well understood and that are being modified by global change. This review attempts to illustrate how fishing activities, aquaculture and climate change are challenging these connections and the consequent health risks and benefits posed to citizens. Although global change may provide some positive aspects for human health locally, such as new sources of omega-3, overall it will exacerbate existing seafood security and safety concerns. Unsustainable fishing and aquaculture practices, and climate change, particularly sea warming, ocean acidification and changes in riverine runoff, are threatening not only the protein and fish oil/omega-3 supplies available for consumers, but also raising ecological and health concerns associated with the increase of contaminants, microbes and biotoxins. In this context, we propose a number of management measures that could mitigate the negative effects of global change on seafood, and hence on human health and well-being.