Trade and Investment Agreements (TIAs) have been widely criticized for their potentially negative effects on health. Many governments, particularly from low- and middle-income countries, have voiced concerns that mega-regional agreements such as the Trans-Pacific Partnership agreement, and the Transatlantic Trade and Investment Partnership, will erode governments’ scope for health protection, weakening for instance those options that remain permissible under World Trade Organization rules. Further, these mega-regional agreements will set default standards and rules of the game that even non-signatories will need to emulate in order to be competitive in the global market. This article begins by reviewing the changing structure of trade and investment policy, global production, and the relation between the two. The effects of trade and investment agreements on health are then analyzed, based on some of the most relevant evidence. Key power asymmetries within the global trade and investment architecture are described, and the way they influence how trade rules are made, implemented and adjudicated. Section 5 examines a particularly striking and topical instance of such power asymmetries, investor-state dispute settlement provisions in TIAs, and their relevance to health. The article concludes with recommendations to mitigate the potential negative health externalities of TIAs.