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The advancements in “omics” (proteomics, genomics, lipidomics, and metabolomics) technologies have yielded large inventories of genes, transcripts, proteins, and metabolites. The challenge is to find out how these entities work together to regulate the processes by which cells respond to external and internal signals. Mathematical and computational modeling of signaling networks has a key role in this task, and network analysis provides insights into biological systems and has applications for medicine. Here, we review experimental and theoretical progress and future challenges toward this goal. We focus on how networks are reconstructed from data, how these networks are structured to control the flow of biological information, and how the design features of the networks specify biological decisions.