Dipeptidyl peptidase 4 (DPP-4) inhibitors are a new class of drugs introduced in 2006 for treatment of type 2 diabetes. In clinical trials lasting up to 2 years, these agents are well tolerated. Incidence of hypoglycemia associated with the use of DPP-4 inhibitors is similar to placebo, but is markedly increased when used in conjunction with sulfonylureas (SUs). DPP-4 inhibitors have neutral effect on body weight but their combination with a thiazolidinedione (TZD) results in slight weight gain averaging 0.5 to 1.3 kg compared with placebo. Other adverse effects recorded more commonly with DPP-4 inhibitors versus placebo are mild, and include nasopharyngitis, headache, and possibly urinary tract infections (UTIs). In the postmarketing period, new adverse effects are reported such as angioedema, increased rates of infection, and skin toxicity. Pancreatitis is inconsistently reported in relationship to sitagliptin, and one analysis links this agent to elevated risk of pancreatic cancer. Pancreatitis is also a rare adverse effect observed in linagliptin clinical studies. There is no evidence that DPP-4 inhibitors increase cardiovascular events or death. Overall, although short-term safety of DPP-4 inhibitors is reassuring, their safety needs to be established by long-term clinical trials and close surveillance during the postmarketing period.