The protein phosphatase 2A [PP2A] family of enzymes has been implicated in the regulation of a variety of cellular functions including hormone secretion, growth, survival and apoptosis. PP2A accounts for ∼1% of total cellular protein and ∼ 80% of total serine/threonine phosphatases, thus representing a major class of protein phosphatases in mammalian cells. Despite significant advances in our current understanding of regulation of cellular function by PP2A under physiological conditions, little is understood with regard to its regulation under various pathological conditions, such as diabetes. Emerging evidence suggests hyperactivation of PP2A in liver, muscle, retina and the pancreatic islet under the duress of glucolipotoxicity and diabetes. Interestingly, pharmacological inhibition of PP2A or siRNA-mediated depletion of the catalytic subunit of PP2A [PP2Ac] levels largely restored PP2A activity to near normal levels under these conditions. Herein, we provide an overview of PP2A subunit expression and activity in in vitro and in vivo models of glucolipotoxicity and diabetes, and revisit the existing data, which are suggestive of alterations in post-translational methylation, phosphorylation and nitration of PP2Ac under these conditions. Potential significance of hyperactive PP2A in the context of cell function, survival and apoptosis is also highlighted. It is hoped that this commentary will provide a basis for future studies to explore the potential for PP2Ac as a therapeutic target for the treatment of diabetes and other metabolic disorders.