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Specific interactions within the cell must occur in a crowded environment and often in a narrow time-space framework to ensure cell survival. In the light that up to 10% of individual protein molecules present at one time in mammalian cells mediate signal transduction, the establishment of productive, specific interactions is a remarkable achievement. The spindle assembly checkpoint (SAC) is an evolutionarily conserved and essential self-monitoring system of the eukaryotic cell cycle that ensures the high fidelity of chromosome segregation by delaying the onset of anaphase until all chromosomes are properly bi-oriented on the mitotic spindle. The function of the SAC involves communication with the kinetochore, an essential multiprotein complex crucial for chromosome segregation that assembles on mitotic or meiotic centromeres to link centromeric DNA with microtubules. Interactions in the SAC and kinetochore-microtubule network often involve the reversible assembly of large multiprotein complexes in which regions of the polypeptide chain that exhibit low structure complexity undergo a disorder-to-order transition. The confinement and high density of protein molecules in the cell has a profound effect on the stability, folding rate, and biological functions of individual proteins and protein assemblies. Here, I discuss the role of large and highly flexible surfaces that mediate productive intermolecular interactions in SAC signaling and postulate that macromolecular crowding contributes to the exquisite regulation that is required for the timely and accurate segregation of chromosomes in higher organisms., (© 2014 Elsevier Inc. All rights reserved.)