There is increasing evidence across disciplines for multiprotein complexes as a mechanism for signal transduction in various cell types. These multiprotein complexes appear to be altered as a direct mechanism to confer signaling responses and to alter phenotype. Although classical experimental techniques are effective to delineate the signaling role of one or a few molecules, they are limited in their ability to thoroughly characterize multiprotein complexes. In this review, the contribution of functional proteomics to a protein complex-based portrait of cardiac cell signaling will be examined along with a discussion and brief evaluation of the state-of-the-art proteomic approaches for multiprotein complex analysis.