A balanced circadian rhythm requires intricate control of transcription regulatory networks, including regulated expression of the clock protein cryptochrome (CRY). By screening a library of ∼60,000 small molecules for their effects on circadian rhythm in mammalian cell lines, Hirota et al. identify the small molecule KL001 as a specific inhibitor of CRY degradation. They show that KL001 targets an E3 ligase that normally mediates CRY turnover, and KL001 therefore triggers a longer circadian period. By combining mathematical modelling and treatment of Cry1- or Cry2-knockout cells with KL001, they were able to show that the two CRY isoforms have a common role in regulation of period length. Finally, the effects of KL001 in blocking gluconeogenesis triggered by glucagon in primary hepatocytes showed that this inhibitor may have relevance for diabetes treatment.