The bioactive sphingolipids ceramide, sphingosine and sphingosine-1-phosphate (S1P) are important signalling molecules that regulate a diverse array of cellular processes. Most notably, the balance of the levels of these three sphingolipids in cells, termed the ‘sphingolipid rheostat’, can dictate cell fate, where ceramide and sphingosine enhance apoptosis and S1P promotes cell survival and proliferation. The sphingosine kinases (SKs) catalyse the production of S1P from sphingosine and are therefore central regulators of the sphingolipid rheostat and attractive targets for cancer therapy. Two SKs exist in humans: SK1 and SK2. SK1 has been extensively studied and there is a large body of evidence to demonstrate its role in promoting cell survival, proliferation and neoplastic transformation. SK1 is also elevated in many human cancers which appears to contribute to carcinogenesis, chemotherapeutic resistance and poor patient outcome. SK2, however, has not been as well characterized, and there are contradictions in the key physiological functions that have been proposed for this isoform. Despite this, many studies are now emerging that implicate SK2 in key roles in a variety of diseases, including the development of a range of solid tumours. Here, we review the literature examining SK2, its physiological and pathophysiological functions, the current knowledge of its regulation, and recent developments in targeting this complex enzyme.