Neuronal circadian oscillators in the mammalian and Drosophila brain express a circadian clock comprised of interlocking gene transcription feedback loops. The genetic clock regulates the membrane electrical activity by poorly understood signaling pathways to generate a circadian pattern of action potential firing. During the day, Na+ channels contribute an excitatory drive for the spontaneous activity of circadian clock neurons. Multiple types of K+ channels regulate the action potential firing pattern and the nightly reduction in neuronal activity. The membrane electrical activity possibly signaling by changes in intracellular Ca2+ and cyclic adenosine monophosphate (cAMP) regulates the activity of the gene clock. A decline in the signaling pathways that link the gene clock and neural activity during aging and disease may weaken the circadian output and generate significant impacts on human health.