Leukocytes are arguably the most motile cells in metazoans. Besides their well-described ability to migrate rapidly toward sites of tissue injury, tissue-specific macrophages migrate already during embryogenesis, when they take up residence in a wide range of organs. The recent identification of molecules responsible for the guidance of leukocytes during development and in response to injury has revealed that these modes of migration are under the control of surprisingly different signaling systems. While the developmental migrations are regulated by hard-wired pre-patterns of secreted proteins, the rapid acute response to injury involves signals like hydrogen peroxide or extracellular nucleotides such as ATP. Ongoing work aims to understand how these distinct signals are integrated in the cell to determine different cellular responses.