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Sleep and metabolism are intertwined physiologically and behaviorally, but the neural systems underlying their coordination are still poorly understood. The hypothalamus is likely to play a major role in the regulation sleep, metabolism, and of their interaction, and increasing evidence suggests that hypocretin cells in the lateral hypothalamus may provide particularly important contributions. Here we review: 1) direct interactions between biological arousal and metabolic systems in the hypothalamus, and 2) indirect interactions between these two systems mediated by stress or reward, emphasizing the role of hypocretins. An increased understanding of the mechanisms underlying these interactions may provide novel approaches for the treatment of patients with sleep disorders and obesity, as well as suggest new therapeutic strategies for symptoms of aging, stress, or addiction.