Quinone reductase 2 (NQO2) is a FAD-linked enzyme that cannot use the common reducing cofactors, NADH and NADPH, for efficient catalysis. This is unusual for an oxidoreductase, particularly since it is a member of a large family of enzymes that all use NAD(P)H efficiently to catalyse the two-electron reduction in quinones and other electrophiles. The inability of NQO2 to use NAD(P)H efficiently raises questions about its cellular function: it remains unclear whether the main cellular role of NQO2 is the catalytic reduction in quinones or whether it is a pseudo-enzyme with other roles such as cell signalling. Intriguingly, NQO2 has been identified as an off-target interactor with over 30 kinase inhibitors and other drugs and natural products. The interaction between NQO2 and kinase-targeted drugs is particularly intriguing because it suggests that NQO2 may be contributing to the cellular effects of these drugs. In this review, we will discuss the enzymatic properties of NQO2, its structure and complexes with various drugs and small molecules, potential cellular roles, and some of the enigmatic findings that make this molecule so interesting and worthy of further investigation.