The Netrin, Slit, Semaphorin, and Ephrin families of secreted proteins were originally characterized in the nervous system as guidance cues for axons; however, recent studies demonstrate that many members of these families contribute to the development of a variety of organs. Here, the current knowledge of their roles is discussed with a focus on four tissues: lung, mammary, cardiovascular, and kidney. While many studies indicate a role for "axon guidance" cues in regulating cell-cell and cell-extracellular matrix (ECM) interactions during organogenesis, there is accumulating evidence that they also contribute to tissue development by regulating the transcription and translation of genes encoding key morphogenetic factors.