Adopting a social science perspective and qualitative methodology on the problem of laboratory fish welfare, this paper examines some underlying social factors and drivers that influence thinking, priorities and implementation of fish welfare initiatives and the 3Rs (Replacement, Reduction and Refinement) for fish. Drawing on original qualitative interviews with stakeholders, animal technologists and scientists who work with fish—especially zebrafish—to illustrate the case, this paper explores some key social factors influencing the take up of the 3Rs in this context. Our findings suggest the relevance of factors including ambient cultural perceptions of fish, disagreements about the evidence on fish pain and suffering, the discourse of regulators, and the experiences of scientists and animal technologists who develop and put the 3Rs into practice. The discussion is focused on the UK context, although the main themes will be pertinent around the world.