Chemotaxis plays a key role in immune response, wound healing, angiogenesis, and embryogenesis as well as mediating cancer metastasis. Research in Dictyostelium discoideum has shown that chemoattractants are sensed by GPCRs and rapidly trigger a complex network of signaling pathways. Our strategy is to use the genetics of Dictyostelium to discover mechanisms by which cells sense chemical gradients and to apply this information to other eukaryotic cells such as human neutrophils and epithelial cells. We found that cell motility depends on spontaneous activation of the signal transduction network and that directional cues bias the activation. Cell motility results from coupling of signal transduction and cytoskeletal networks. The signal transduction network, comprised of multiple pathways that include Ras GTPases, PI(3)K and Rac GTPases is excitable, exhibiting wave propagation, refractoriness and maximal response to suprathreshold stimuli, even in the absence of a funtional cytoskeleton. We have been able to exploit the excitable nature of the signal transduction network to force cells into different modes of migration. When the threshold of the excitable network is lowered in amoeboid cells, they first transition to a “fan” mode resembling the movement of a keratocyte. They then begin to display slow global oscillations, and finally they assume an extremely flattened “pancake” mode. Thus, the set point of the excitable signal transduction network controls the type of protrusion cells make and how they move. We are now working on the idea that chemoattractants and other cues such as mechanical forces are integrated to modulate the setpoint differently at the front and rear of migrating cells. .