Cell migration requires establishment of a single pseudopodium in the direction of movement. Here we highlight recent advances in our understanding of the molecular signaling mechanisms that regulate formation of pseudopodia. We discuss how signal transduction processes are spatially and temporally organized to establish cell polarity through directed extension and stabilization of dominant pseudopodia. We also highlight recent advances in technology that will further the understanding of signaling dynamics specific to pseudopodia extension and cell migration.