Following the discovery of insulin 85 yr ago and the realization thereafter that in some individuals, tissues lose their responsiveness to this hormone, an enormous world-wide effort began to dissect the cellular mechanisms of insulin action and define abnormalities in the insulin-resistant state. A clear goal through the years has been to unravel the insulin signal transduction network regulating glucose transport. This line of investigation has provided tremendous insight into the physiology and pathophysiology surrounding the cellular processes controlled by insulin. Between the plasma membrane insulin receptor and the intracellularly sequestered insulin-responsive glucose transporter GLUT4, many events participate in the transduction of the insulin signal. In this review, we detail our current state of knowledge on the intricate insulin signaling network responsible for glucose transport in peripheral adipose and skeletal muscle tissues. In particular, we identify signaling connections spanning the insulin receptor and GLUT4. In addition, we discuss cytoskeletal mechanics and membrane docking and fusion mechanisms pertinently involved in the cellular redistribution of GLUT4 to the plasma membrane. On the whole, this review highlights the considerable progress in our understanding of insulin signaling in health and disease as we rapidly approach the centennial anniversary of insulin's discovery.