Chemotaxis, or directed cell movement towards small molecule ligands, is a central function of many cell types and plays a key role in diverse biological processes. This review summarizes our present understanding of the signaling pathways that control the ability of cells to sense the chemoattractant gradient and respond by converting a shallow extracellular gradient into a steep intracellular gradient that leads to formation of a pseudopod in the direction of the chemoattractant gradient and contraction of the cell's posterior. The review focuses on the phosphatidylinositol 3-kinase pathway in Dictyostelium and our understanding of parallel pathways in leukocytes.