The obesity epidemic has resulted in increasingly urgent calls for large-scale prevention strategies. Meanwhile, effective treatment approaches that result in sustainable weight loss are needed to attenuate the cardiometabolic risks that may lead to comorbid illnesses and early mortality. Public education efforts geared toward those afflicted with obesity should emphasize that a relatively modest reduction in body weight dramatically reduces disease risk, thereby improving overall long-term health. Setting realistic weight loss goals with patients should reduce the overwhelming frustration often associated with the belief that large amounts of weight loss are needed for improved health. This misconception often impedes overweight and obese individuals from seeking treatment. Effective strategies are available to help overweight and obese individuals achieve reasonable weight loss goals. Important challenges exist in preventing weight regain following weight loss intervention. Studies are underway to identify new therapeutic strategies to effectively reduce weight, as well as to provide long-term data on successful weight loss maintenance strategies.