Netrins belong to the family of laminin-like secreted proteins, which guide axonal migration and neuronal growth in the developing central nervous system. Over the last 20 years, it has been established that netrin-1 acts as a chemoattractive or chemorepulsive cue in diverse biological processes far beyond neuronal development. Netrin-1 has been shown to play a central role in cell adhesion, cell migration, proliferation, and cell survival in neuronal and non-neuronal tissue. In this context, netrin-1 was found to orchestrate organogenesis, angiogenesis, tumorigenesis, and inflammation. In inflammation, as in neuronal development, netrin-1 plays a dichotomous role directing the migration of leukocytes, especially monocytes in the inflamed tissue. Monocyte-derived macrophages have long been known for a similar dual role in inflammation. In response to pathogen-induced acute injury, monocytes are rapidly recruited to damaged tissue as the first line of immune defense to phagocyte pathogens, present antigens to initiate the adaptive immune response, and promote wound healing in the resolution phase. On the other hand, dysregulated macrophages with impaired phagocytosis and egress capacity accumulate in chronic inflammation sites and foster the maintenance-and even the progression-of chronic inflammation. In this review article, we will highlight the dichotomous roles of netrin-1 and its impact on acute and chronic inflammation.