Circadian rhythms are generated by complex interactions among genes and proteins. Self-sustained ∼24 hour oscillations require negative feedback loops and sufficiently strong nonlinearities that are the product of molecular and network switches. Here we review common mechanisms to obtain switch-like behavior, including cooperativity, antagonistic enzymes, multisite phosphorylation, positive feedback, and sequestration. We discuss how network switches play a crucial role as essential components in cellular circadian clocks, serving as integral parts of transcription-translation feedback loops (TTFLs) that form the basis of circadian rhythm generation. The design principles of network switches and circadian clocks are illustrated by representative mathematical models that include bistable systems and negative feedback loops combined with Hill functions. This work underscores the importance of negative feedback loops and network switches as essential design principles for biological oscillations, emphasizing how an understanding of theoretical concepts can provide insights into the mechanism generating biological rhythms.

network switches

ultrasensitivity

bistability

feedback loops

circadian clock

mathematical models

transcription-translation feedback loop

mitogen-activated protein kinase

intrinsically-disordered protein

familial sleep phase syndrome

ordinary differential equation

delay differential equation

© 2024 THE AUTHORS. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology.