Directed cell migration is critical for normal development, immune responses, and wound healing and plays a prominent role in tumor metastasis. In eukaryotes, cell orientation is biased by an external chemoattractant gradient through a spatial contrast in chemoattractant receptor-mediated signal transduction processes that differentially affect cytoskeletal dynamics at the cell front and rear. Mechanisms of spatial gradient sensing and chemotaxis have been studied extensively in the social amoeba Dictyostelium discoideum and mammalian leukocytes (neutrophils), which are similar in their remarkable sensitivity to shallow gradients and robustness of response over a broad range of chemoattractant concentration. Recently, we have quantitatively characterized a different gradient sensing system, that of platelet-derived growth factor-stimulated fibroblasts, an important component of dermal wound healing. The marked differences between this system and the others have led us to speculate on the diversity of gradient sensing mechanisms and their biological implications.