Netrins are a family of laminin-like proteins, which were initially identified for their role in embryonic axonal guidance. Over recent years, it has become apparent that netrin-1 may additionally be involved in the underlying pathology of several multisystem diseases, making it an attractive potential therapeutic target. It is involved in postnatal angiogenesis, particularly in the context of an ischaemic insult, although there are conflicting reports as to whether netrin-1 acts in a pro- or anti-angiogenic capacity. In atherosclerosis, opposing effects have similarly been reported on plaque progression, due to the ability of netrin-1 to inhibit both macrophage egress from and monocyte ingress into lesions. Netrin-1 has also been shown to exert a cardioprotective action in the context of ischaemia–reperfusion injury following myocardial infarction. Moreover, urinary netrin-1 levels rise in response to acute kidney injury and at a faster rate than traditional markers of renal impairment, highlighting a potential clinical role for netrin-1 as a biomarker of renal function. The increased urinary excretion of netrin-1 during kidney disease is paralleled by a down-regulation of its plasma levels, with potential implications at a systemic level. In summary, the role of netrin-1 in cardiovascular disease is an emerging area of research requiring further in-depth study to elucidate its mechanism of action and potential as a therapeutic target, especially in view of its seemingly contradictory actions in certain physiological pathways which serve to highlight its manifold and often opposite effects in numerous physiological and pathophysiological processes.