: Kinases play central roles in signaling cascades, relaying information from the outside to the inside of mammalian cells1. De novo designed protein switches capable of interfacing with tyrosine kinase signaling pathways would open new avenues for controlling cellular behavior, but to date no such systems have been described. Here we describe the de novo design of two classes of protein switches which link phosphorylation by both tyrosine and serine kinases to protein-protein association. In the first class, protein-protein association drives kinase phosphorylation; addition of a designed co-regulator induces the phosphorylation of the ITAM motif central to T-cell signaling2. In the second class, kinase phosphorylation drives protein-protein association; we describe systems in which kinase action drives reconstitution of GFP fluorescence from fragments and the inhibition of the protease calpain. The designed switches are reversible and function in vitro and in cells with up to 40-fold activation of switching by phosphorylation.