The S. cerevisiae SCF^Cdc4p ubiquitin–protein ligase complex promotes cell cycle transitions through degradation of cell cycle regulators. To investigate SCF^Cdc4p regulation in vivo, we examined the stability of individual SCF^Cdc4p components. Whereas Cdc53p and Skp1p were stable, Cdc4p, the F box–containing component responsible for substrate recognition, was short lived and subject to SCF-mediated ubiquitination. Grr1p, another F box component of SCF complexes, was also ubiquitinated. A stable truncated Cdc4p^F-β-gal hybrid protein capable of binding Skp1p and entering into an SCF complex interfered with proteolysis of SCF targets and inhibited cell proliferation. The finding that the F box–containing SCF components are unstable suggests a mechanism of regulating SCF function through ubiquitination and proteolysis of F box components.