Over the past ten years, tremendous advances in our understanding of the role of the hypothalamic neurohormone, melanin-concentrating hormone (MCH), and its involvement in the regulation of food intake and body weight have been achieved. The MCHR1 receptor has been actively targeted as a much-needed, novel treatment for obesity, a disease of epidemic proportion in the United States. Numerous companies have joined the competition to be the first to produce a small molecule antagonist targeting MCHR1 receptors in the race for therapeutics for this disease. This review details the rising need for new treatments for obesity; the rationale and target validation of MCHR1 receptor antagonists as potential treatments for this disease; and the current status of the numerous small molecule MCHR1 antagonists in development by different companies. MCHR1 antagonists might find an additional usage in the treatment of anxiety and depression disorders. The rationale and current status of this effort by several companies is also reviewed.