In the 1980s, Mike Young and Michael Rosbash along with Jeff Hall began to use the fruit fly Drosophila for molecular studies of the circadian clock. Earlier genetic work in this organism by Konopka and Benzer had shown that profound changes in circadian rhythmicity accompanied mutations of the fly’s period gene. Our fly studies and work from other investigators identified additional genes as well as proteins and mechanisms essential for circadian rhythmicity. Most of these principles operate in vertebrates, within single cells, and influence most aspects of physiology. Mutations in orthologs of fly clock genes even alter the timing of human sleep/wake cycles. We will discuss these principles as well as future challenges in circadian research for young investigators.