The sleep-wake cycle is regulated through circadian clocks that drive the near-24 hrs rhythmicity of many physiological processes and sleep homeostasis that determines the sleep duration required per day. The discovery of core circadian clock components was initiated by the finding of period gene that controls the clock speed bidirectionally. On the other hand, it is still unknown whether there is a single gene that controls sleep duration bidirectionally. We focused on the role of Ca2+/calmodulin-dependent kinase II (CaMKII) in the regulation of sleep duration. We reported this enzyme as a sleep-promoting kinase by showing that the knock-out of Camk2a or Camk2b results in the significant reduction of sleep duration in mice (Tatsuki et al. Neuron 2016). CaMKIIα/β dodecamer is activated by Ca2+/CaM and undergoes a large scale conformational change. The conformational change exposing the kinase domain affects the protein-protein interaction between CaMKIIα/β and other binding partners. The exposure of the kinase domain also triggers the auto-phosphorylation that stimulates or suppresses the kinase activity of CaMKIIα/β, depending on the phosphorylation sites. In this presentation, we will introduce our recent study aiming to understand what biochemical property of CaMKIIα/β is most prominent to control the sleep duration and to create a gain-of-function mutant of CaMKIIα/β that can, contrary to the phenotype of Camk2a/b knock-out, lengthen the sleep duration.