The budding yeast gene product, CDC53p, forms E3-like SCF complexes with SKP1 and F-box-containing proteins to mediate the ubiquitin-dependent degradation of G1 cyclins and cyclin-dependent kinase (CDK) inhibitors. Cdc53 represents a multigene family, the human homologues of which, the cullin family, include at least six distinct members. We have found that human cullin 1, but not the other closely related cullins 2, 3, 4A, and 5, selectively interacts with human SKP1. This CUL1-SKP1 interaction is mediated by the NH2-terminal domains of both proteins, and the association appears to be required for the interaction of CUL1 with SKP2, an essential element of the S-phase cyclin A-CDK2 kinase. In an asynchronous population of dividing cells, a minor amount of CUL1 specifically associates with cyclin A but not with other cyclins or CDK inhibitors. The steady-state levels of both CUL1 and SKP1 as well as their association with one another remain relatively constant throughout the cell cycle and in postmitotic cells. Our findings indicate that the SCF pathway, although similarly used by the mammalian cullin 1, is not shared by other cullin members. This implies that most cullins may use a SKP1/F-box-independent pathway to facilitate protein degradation.