GSK3 has been implicated in the development of insulin resistance, primarily based on its role in regulation of glycogen synthesis. However, GSK3 is involved in many other important signaling cascades which may regulate glucose homeostasis and the development of insulin resistance. In addition, GSK3 is composed of two isoforms, GSK3alpha and beta, which do not completely share their physiological roles, and this raises a possibility that GSK3alpha and beta may function differently in glucose homeostasis. In this review, we will give an overview to examine potential mechanisms for the roles of GSK3 in the development of insulin resistance.