Recent studies suggest that secreted proteins in several families of axon guidance molecules, the slits, the semaphorins and the netrins may play important roles in cancers. The expression of many of these proteins is either down-regulated or up-regulated in cancer cell lines and tumors. Several of the corresponding genes are localized on chromosomal regions associated with frequent loss-of-heterozygosity and their promoters are hypermethylated, suggesting that they may act as tumor suppressors. Moreover, many axon guidance proteins were also shown to control the development of the vasculature and may thus control angiogenesis in the tumors. These axon guidance molecules may also control the migration and invasion potential of cancer cells. Lastly, they could stimulate their proliferation and regulate cell death. Thus, axon guidance molecules appear as good targets for the development of novel therapeutic agents for the treatment of malignancy.