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Signaling pathways are crucial for cell differentiation and response to cellular environments. Recently, a large number of approaches for the global analysis of genes and proteins have been described. These have provided important new insights into the components of different pathways and the molecular and cellular responses of these pathways. This review covers genomic and proteomic (collectively referred to as ‘omic’) approaches for the global analysis of cell signaling, including gene expression profiling and analysis, protein–protein interaction methods, protein microarrays, mass spectroscopy and gene-disruption and engineering approaches.