Awakening from sleep is a clear example of an event for which (biological) clocks are of great importance. We will review some major pathways the mammalian biological clock uses to ensure an efficient and coordinated wake-up process. First we show how this clock enforces daily rhythmicity onto the hypothalamo-pituitary-adrenal (HPA) axis, via projections to neuroendocrine neurons within the hypothalamus. Next we demonstrate how this brain clock controls plasma glucose concentrations, via projections to sympathetic and parasympathetic pre-autonomic neurons within the hypothalamus. Orexin neurons in the lateral hypothalamus appear to be an important hub in this awakening control network.