The purpose of this paper is to offer a critical approach to the theory of autopoiesis in order to see how it challenges mainstream Darwinism. In the first part of the paper, I characterize Darwinism from the concepts of natural selection, heredity, reproduction, and evolution. This characterization is absolutely schematic, and I hope not controversial at all, since my aim is to provide a general background for the discussion of the rest of the paper. The second part presents the main tenets of the theory of autopoiesis, also paying special attention to the concepts of natural selection, heredity, reproduction, and evolution. The third and final part considers some criticisms that have been directed against the theory and suggests some new ones. As I said, my intention is to offer a critical approach, so that I pretend to assess neither autopoiesis nor Darwinism. The assessment, it seems to me, would be a matter of scientific debate—not properly of philosophy. Therefore, given that my approach attempts to be a conceptual clarification, my contribution to the contemporary debate about Darwinism is twofold. On the one hand, I show that conceptually autopoiesis constitutes an important challenge to Darwinism, but on the other, I also show that some fundamental aspects of the theory appear to be both epistemologically and empirically problematic, which perhaps helps to understand why autopoiesis is not widely accepted in mainstream Darwinism.