The notion that all protein functions are determined through macromolecular interactions is the driving force behind current efforts that aim to solve the structures of all cellular complexes. Recent findings, however, demonstrate a significant amount of structural disorder or polymorphism in protein complexes, a phenomenon that has been largely overlooked thus far. It is our view that such disorder can be classified into four mechanistic categories, covering a continuous spectrum of structural states from static to dynamic disorder and from segmental to full disorder. To emphasize its generality and importance, we suggest a generic term, ‘fuzziness’, for this phenomenon. Given the crucial role of protein disorder in protein–protein interactions and in regulatory processes, we envision that fuzziness will become integral to understanding the interactome. The notion that all protein functions are determined through macromolecular interactions is the driving force behind current efforts that aim to solve the structures of all cellular complexes. Recent findings, however, demonstrate a significant amount of structural disorder or polymorphism in protein complexes, a phenomenon that has been largely overlooked thus far. It is our view that such disorder can be classified into four mechanistic categories, covering a continuous spectrum of structural states from static to dynamic disorder and from segmental to full disorder. To emphasize its generality and importance, we suggest a generic term, ‘fuzziness’, for this phenomenon. Given the crucial role of protein disorder in protein–protein interactions and in regulatory processes, we envision that fuzziness will become integral to understanding the interactome. β-catenin binding domain of Tcf4. cell-division cycle 4 protein, an E3 ubiquitin ligase that targets Sic1, a cyclin-dependent kinase (Cdk) inhibitor, for degradation. cystic fibrosis transmembrane conductance regulator, a phosphorylation-regulated Cl− channel in the epithelial cell membrane. cyclic AMP response element-binding protein, a transcription factor responding to elevated cAMP levels. C-terminal domain of proteins. DNA fragmentation factor 40, responsible for internucleosomal DNA cleavage during the terminal stages of programmed cell death. dihydropyridine receptor, a Ca++ channel in the sarcoplasmic reticulum membrane of skeletal muscle, the primary sensor of action potential depolarization in excitation–contraction coupling. Ewing's sarcoma (EWS) fusion protein, generated by chromosomal translocations of the EWS oncogene in distinct human cancers. fibronectin-binding protein, a bacterial cell-wall anchored protein that binds to the extracellular matrix of the host. fusion 3 protein, a mitogen-activated protein kinase (MAPK) in the mating (pheromone) response MAPK cascade in S. cerevisiae. heat-shock protein 25, a member of the small heat-shock protein family, a chaperone. heat-shock protein 90, one of the best-characterized chaperones. inhibitor of aspartic proteinase A in S. cerevisiae. kinase-inducible domain of CREB transcription factor. domain of CREB-binding protein (CBP), which binds to the KID domain of CREB. nuclear localization signal, a short motif that directs the protein into the nucleus. octamer-binding factor 1, a transcription factor that stimulates transcription of immunoglobulin genes. Pit-1, Oct-1, Oct-2, Unc-86; helix-turn-helix DNA-binding domain. protein phosphatase 5, involved in cellular proliferation, migration, differentiation and survival. infectious protein, able to undergo autocatalytic, self-sustaining transition to the amyloid state. RNA polymerase II, a large multiprotein complex that transcribes protein-coding genes in eukaryotes. ryanodine receptor, a Ca++ channel in the sarcoplasmic reticulum membrane of skeletal muscle functioning in excitation–contraction coupling. splicing factor 1, a protein involved in the initial steps of pre-mRNA splicing. domain = Src-homology domain 3, a domain to which proline-rich sequences bind, often involved in protein–protein interactions in signalling pathways. S-phase Cdk inhibitor 1, implicated in the transition from G1 to S phase in yeast. promoter-specific factor 1, a zinc finger transcription factor that binds to GC box promoter elements. sterile 5 protein, a scaffold protein functioning in the mating (pheromone) response MAPK cascade in S. cerevisiae. transactivator domain, the domain of transcription factors that interacts with components of the general transcription machinery. T cell factor 4, a transcription factor of the Tcf–LEF family involved in Wnt signalling, stem cell replication and differentiation. tetratricopeptide domain, an alpha-helical repeat domain often involved in protein–protein interactions.