Regulated interactions between proteins govern signaling pathways within and between cells. Structural studies on protein complexes formed reversibly and/or transiently illustrate the remarkable diversity of interactions, both in terms of interfacial size and nature. In recent years, "domain-peptide" interactions have gained much greater recognition and may be viewed as both pre-translational and posttranslational-dependent functional switches. Our understanding of the multistep regulation of auto-inhibited multidomain proteins has also grown. Their activity may be understood as the "combinatorial" output of multiple input signals, including phosphorylation, location, and mechanical force. The prospects for bridging the gap between the new "systems biology" data and the traditional "reductionist" data are also discussed.