High-throughput screening technologies allow the identification of genes and proteins essential for mammalian cell division. However, the underlying complexity and connectivity of different biological processes, such as signal transduction, transcription, translation and proteolysis make it difficult to understand the mammalian cell cycle based on the analysis of its individual components alone. The recent development of robust and precise assays to study the mammalian cell cycle, in combination with functional genomics and proteomics, together provide the necessary tools to address this critical issue. With the implementation of different "Omics" technologies for quantitative and high-throughput data acquisition, the possibility of obtaining a more detailed view of the mammalian cell cycle is now realistic. Here, we review RNAi reagents, assays and validation strategies for the identification of genes functioning in the human cell cycle, and outline genomic, proteomic and microscopic approaches to further characterize their specific functions. While a fully integrated model of mammalian cell division remains a distant goal, a framework of a systems understanding of this medically relevant process is beginning to emerge.