Insulin resistance in peripheral tissues is the primary cause responsible for onset of type II diabetes mellitus. Recently, the genetic and biochemical dissection of intracellular signalling pathways transducing the metabolic and mitogenic effects of insulin has contributed to the understanding of the molecular causes of this insulin resistance. In particular, important efforts have been developed to comprehend the role of negative regulators of insulin signalling, since they might represent future therapeutical targets to reduce insulin resistance in peripheral tissues. Herein, we will briefly review major intracellular signalling pathways activated by insulin and how they are negatively regulated by distinct mechanisms. In particular, the role of PTEN and SHIP2, two phosphoinositide phosphatases recently implicated as negative modulators of insulin signalling, is in focus. Current knowledge on the role of PTEN and SHIP2 in insulin resistance, type II diabetes and related disorders will also be discussed.