Obesity is a major risk factor for diabetes and cardiovascular disease, and most people with diabetes are overweight or obese. Weight reduction has been shown to improve glycemic control and reduce cardiovascular risk in the diabetic population. While physicians strive to achieve better glycemic control for their patients with diabetes, they are faced with the problem of weight gain that is commonly encountered with the use of antidiabetic agents, particularly insulin, insulin secretagogues, and thiazolidinediones. Weight gain in this population could offset the beneficial effects of good glycemic control and discourage patients from adhering to treatment. In this review, we discuss the effects of the various antidiabetic agents on body weight, highlighting the potential mechanisms and the implications of weight gain in this population. We also present the available therapeutic modalities that have the potential of achieving better glycemic control without adverse effects on body weight.