Overall lowering of glucose is of pivotal importance in the treatment of diabetes, with proven beneficial effects on microvascular and macrovascular outcomes. Still, patients with similar glycosylated hemoglobin levels and mean glucose values can have markedly different daily glucose excursions. The role of this glucose variability in pathophysiological pathways is the subject of debate. It is strongly related to oxidative stress in in vitro, animal, and human studies in an experimental setting. However, in real-life human studies including type 1 and type 2 diabetes patients, there is neither a reproducible relation with oxidative stress nor a correlation between short-term glucose variability and retinopathy, nephropathy, or neuropathy. On the other hand, there is some evidence that long-term glycemic variability might be related to microvascular complications in type 1 and type 2 diabetes. Regarding mortality, a convincing relationship with short-term glucose variability has only been demonstrated in nondiabetic, critically ill patients. Also, glucose variability may have a role in the prediction of severe hypoglycemia. In this review, we first provide an overview of the various methods to measure glucose variability. Second, we review current literature regarding glucose variability and its relation to oxidative stress, long-term diabetic complications, and hypoglycemia. Finally, we make recommendations on whether and how to target glucose variability, concluding that at present we lack both the compelling evidence and the means to target glucose variability separately from all efforts to lower mean glucose while avoiding hypoglycemia.