In the life sciences, a new paradigm is emerging that places networks of interacting molecules between genotype and phenotype. These networks are dynamically modulated by a multitude of factors, and the properties emerging from the network as a whole determine observable phenotypes. This paradigm is usually referred to as systems biology, network biology, or integrative biology. Mass spectrometry (MS)–based proteomics is a central life science technology that has realized great progress toward the identification, quantification, and characterization of the proteins that constitute a proteome. Here, we review how MS-based proteomics has been applied to network biology to identify the nodes and edges of biological networks, to detect and quantify perturbation-induced network changes, and to correlate dynamic network rewiring with the cellular phenotype. We discuss future directions for MS-based proteomics within the network biology paradigm.