As type 2 diabetes mellitus progresses, multiple antihyperglycemic agents are needed to maintain adequate glycemic control. Consensus guidelines recommend combining agents with complementary mechanisms of action. Given that hypoglycemic events increase the risk of cardiovascular disease and that weight gain affects mortality in obese individuals, it is important to control hyperglycemia without inducing hypoglycemia or weight gain. Peer-reviewed clinical trial data from patients requiring insulin-containing combination therapy suggest that insulin may be more effective at controlling hyperglycemia when given with appropriate combination therapy, but insulin is associated with weight gain and hypoglycemia. Some agents should not be combined with insulin because of associated weight gain and edema (ie, thiazolidinediones) or hypoglycemia (ie, sulfonylureas). Conversely, the lack of weight gain and hypoglycemia associated with metformin, glucagon-like peptide-1 agonists and dipeptidyl peptidase-4 inhibitors and suppression of glucagon secretion by both classes of incretin-based therapies suggest that these agents are well suited to combination therapy with insulin.