The strength and duration of intracellular signals must be precisely regulated, since inappropriate signaling can cause disease. Negative feedback mechanisms provide an effective means of controlling growth factor-mediated signaling, either by restricting the incoming signal or by inducing counter-regulatory mechanisms affecting signal propagation. Sef proteins represent a new class of feedback antagonists capable of regulating receptor tyrosine kinase signaling. The involvement of Sef in development, as well as in other biological processes, was demonstrated by biochemical and genetic approaches.