Organisms across all kingdoms of life have an internal 24-hour timekeeping mechanism known as circadian rhythms. In mammals, circadian rhythms arise from interlocking transcription-translation feedback loops which include the transcription factor CLOCK:BMAL1 driving the transcription of key repressors such as cryptochrome (CRY1 and CRY2) and period (PER1 and PER2). CRY1 and CRY2 are both similarly composed of a conserved structured domain known as the photolyase homology region (PHR) that is tethered to an intrinsically disordered C-terminal tail. While the PHR is necessary and sufficient to directly interact with CLOCK:BMAL1 to induce repression, the C-terminal tails also play a role in regulating circadian timing. In other CRY homologs such as Drosophila CRY, the PHR and C-terminal tail reversibly bind each other to create an autoinhibited conformation. In this study, we demonstrate how interactions with CRY molecules (e.g. CLOCK interacting with CRY1/2) and interactions within a CRY protein molecule (e.g. the PHR-tail interaction) regulate circadian rhythms interactions. In Chapter 2, we describe how CRY1 and CRY2 play divergent roles in circadian timing due to structural differences in the secondary pockets of CRY1 and CRY2 that lead to differences in how strongly CRY1 or CRY2 interact with CLOCK. In Chapter 3, we determined that the CRY1 C-terminal tail makes an autoinhibitory interaction with the CRY1 PHR and inhibits the CRY1–CLOCK interaction at the secondary pocket. We also found that CRY1Δ11 (a prevalent mutation that extends circadian period and causes delayed sleep phase disorder) enhances the interaction between CRY1 and CLOCK by removing an autoinhibitory region on the CRY1 tail. In Chapter 4, we describe work with collaborators and identify how a cancer-related CRY2 mutation alters circadian timing by weakening the interaction between CRY2 and CLOCK at the secondary pocket. In the final chapters of this dissertation, we describe how small molecules that target interactions “with and within” CRYs can modulate circadian rhythms.