This introductory essay to the special issue “Sexual Difference between Psychoanalysis and Vitalism” provides a genealogy of the concepts of sexual difference in the Western tradition from Kant through Darwin, Freud, Beauvoir, Lévi-Strauss, Lacan, Irigaray, Foucault, Butler, and Deleuze and Guattari. The three main problems running through the essay are how these theorists think of the agency of the biophysical body in the process of sexual differentiation, whether sex is two or a multiplicity, and what the implications are for feminist politics. The essay does not summarize the contributions as they stand very much on their own.