Recent research has shown how federalism affects health care finance, health care reform, and health policy innovation. The purpose of this article is to extend this research program to study the linkages between federalism and technological change. It does so using comparative case studies spanning five countries to examine innovation and diffusion of two blood technologies—enzyme-linked immunosorbent assays (ELISA blood tests) and heat treatment—in response to the threat to the blood supply posed by HIV during the 1980s. Prior research has produced three contradictory models of the federalism-innovation relationship. This article attempts to resolve these contradictions, posits new hypotheses, and highlights sources of omitted variable bias that have important implications for understanding technological change. The case studies show that overall decentralization, rather than federalism alone, aids technological progress by allowing its supporters to “venue shop” around political resistance. Decentralization also makes the state less vulnerable to capture by status-quo interest groups. Moreover, political decentralization may have a positive effect on technological diffusion, but a far weaker effect on innovation. Thus, prior research that conflates these two effects should be revisited.