The CRL1 complex, also known as the SCF complex, is a ubiquitin ligase that in mammals consists of an adaptor protein (SKP1), a scaffold protein (CUL1), a RING finger protein (RBX1, also known as ROC1), and one of about 70 F-box proteins. Given that the F-box proteins determine the substrate specificity of the CRL1 complex, the variety of these proteins allows the generation of a large number of ubiquitin ligases that promote the degradation or regulate the function of many substrate proteins and thereby control numerous key cellular processes. The physiological and pathological functions of these many CRL1 ubiquitin ligases have been studied by the generation and characterization of knockout mouse models that lack specific CRL1 components. In this chapter, we provide a comprehensive overview of these mouse models and discuss the role of each CRL1 component in mouse physiology and pathology.