Treatment of diabetes mellitus with medications, including insulin, sulfonylureas, and thiazolidinediones (TZDs), often leads to weight gain through a variety of mechanisms. Weight gain can have adverse consequences for patients with type 2 diabetes, many of whom are overweight or obese, because obesity is linked to insulin resistance and other medical consequences such as cardiovascular disease. TZDs improve glycemic control and insulin sensitivity in patients with type 2 diabetes, despite their potential to cause weight gain. Studies have attempted to elucidate the mechanisms behind the apparent paradox of TZDs improving insulin sensitivity while causing weight gain. Data indicate that with TZD treatment, there is a favorable shift in fat distribution from visceral to subcutaneous adipose depots that is associated with improvements in hepatic and peripheral tissue sensitivity to insulin. Although weight gain may occur with TZD therapy, it is not inevitable. A weight-management program combining a low-calorie, low-sodium diet with education and behavior modification has been shown to be effective in patients with type 2 diabetes being treated with TZDs. Further research is needed to define the optimal dietary modifications that can be used universally in TZD-treated patients to minimize weight gain while effectively treating insulin resistance and hyperglycemia.