Obesity-related conditions are among the most expensive health care problems, accounting for $92 billion to $117 billion in annual health care costs. Obesity treatment has therefore emerged as a prime focus of health care. However, there is currently no reliable method to consistently attain and sustain weight loss as evidenced by the continually escalating prevalence of overweight/obese adults in the United States, now exceeding 70%. The difficulty many have in decreasing body weight and maintaining weight loss is largely because of a coordinated set of compensatory mechanisms the body uses to resist maintenance of an energy deficit induced by exercise or energy-restricted dieting. By working to maintain energy balance, these compensatory mechanisms represent an important barrier to many individuals' weight loss efforts. For this review, relevant publications were searched via PubMed database using the terms obesity treatment, exercise, energy compensation, compensatory mechanisms, and weight loss. This paper provides an overview of these specific compensatory mechanisms, the physiology driving them, and how different exercise modalities influence energy compensation. There are many sources of energy compensation including metabolic, hormonal, and behavioral, which may either drive eating behaviors or reduce energy expenditure when attempting weight loss. Exercise is a useful weight loss strategy only if these compensatory mechanisms do not completely abolish the negative energy balance produced by exercise. There is evidence that greater amounts of exercise can overcome these compensatory responses to produce significant weight loss without dietary intervention.