Chemokines are cytokines capable of inducing chemotaxis of inflammatory cells in vitro. It is likely that they are also involved in controlling cell migration in vivo, but this and other putative functions have not been properly validated to date. To investigate these functions in vivo, a number of new experimental approaches are required. This mini-review focuses on a set of genetic approaches that can be used to understand chemokine function at the level of the organism. Hopefully, these approaches will help us define the fundamental role of chemokines in development, homeostasis, and disease.