Type 2 diabetes mellitus is a progressive disease characterized by an impairment of insulin action, and failure of pancreatic β-cells to compensate for the enhanced insulin demand. Owing to the progressive nature of the disease, many individuals require insulin replacement therapy to maintain glycemic control. Intensification of treatment in these circumstances usually results in weight gain and increased risk of hypoglycemia, two undesirable events that are associated with a worse cardiovascular risk profile and decreased adherence to treatment. The introduction of glucagon-like peptide-1 (GLP-1) analogs (exenatide and liraglutide) into the diabetes market offers a new therapeutic approach to the treatment of type 2 diabetes. GLP-1 analogs increase insulin secretion and inhibit glucagon secretion in a glucose-dependent manner, thus conferring glycemic control with a low risk of hypoglycemia. GLP-1 analogs also promote weight loss, and have beneficial effects on blood pressure and cardiovascular risk markers. The combination of GLP-1 analogs and insulin might be highly effective to maintain glucose control, and to attenuate the adverse effects usually associated with insulin therapy. Data from both retrospective and prospective clinical studies support the therapeutic potential of the combination of GLP-1 analogs and insulin, usually showing beneficial effects on glycemic control associated with reduced weight gain, low incidence of hypoglycemia and, in established insulin therapy, reduction in insulin dose. In this review, the pathophysiological rationale for using the combination of GLP-1 analogs is discussed, and data from clinical studies that have evaluated the efficacy of this treatment strategy are summarized.