Sleep-wake cycle is controlled by the interplay between circadian rhythm and sleep homeostasis. Genetic studies, through the discovery of mutants with altered sleep-wake behaviors, have explored the molecular components that regulate our daily rhythms. In mammalian circadian clocks, negative-feedback loops composed of a set of transcription activators and inhibitors generate a cell-autonomous oscillation of transcriptional activity. Recent studies further discovered that such transcriptional feedback is controlled through post-translational modifications for the fine-tuning of the oscillation period. Compared to circadian clocks, the canonical molecular model for sleep homeostasis is not established yet. However, recent advances in mammalian forward and reverse genetic studies discovered several genes that regulate sleep duration. Interestingly, these genes include ion channels and kinases, which potentially modify these channels. A part of sleep-related ion channels is involved in Ca2+-dependent hyperpolarization of the neuronal membrane potential. Computational models suggest that the hyperpolarization pathway underlies the firing patterns observed in the cortical pyramidal neurons during sleep. Thus, ion channels controlling the membrane potential of the cortical neurons may be involved in sleep homeostasis.