Skeletal muscle is a major glucose-utilizing tissue in the absorptive state and alterations in muscle insulin-stimulated glucose uptake lead to derangements in whole body glucose disposal. The major glucose transporter expressed in skeletal muscle is the GLUT4 isoform. In the muscle fiber, GLUT4 undergoes insulin-stimulated translocation to T-tubules and to sarcolemma and it represents a pharmacological target for the treatment of diabetes mellitus, insulin-resistant states or in cardiac dysfunction. We review recent studies describing the characterization of the cellular steps followed by GLUT4 in muscle and we propose several working models for an integrated structure of the GLUT4 trafficking pathway.