Today, it is widely accepted that proteins that lack highly defined, globular structures, 3D, termed “intrinsically disordered proteins (IDPs)”, play key roles in myriad biological processes. Our understanding of how intrinsic disorder mediates biological function is, however, incomplete. Here, we review disorder-mediated cell cycle regulation by two intrinsically disordered proteins, p21 and p27. A structural adaptation mechanism involving a stretchable, dynamic linker helix allows p21 to promiscuously recognize the various Cdk/cyclin complexes that regulate cell division. Disorder within p27 mediates transmission of an N-terminal tyrosine phosphorylation signal to a C-terminal threonine phosphorylation, constituting a signaling conduit. These mechanisms are mediated by folding upon binding p21/p27’s regulatory targets. However, residual disorder within the bound state contributes critically to these functional mechanisms. Our studies provide insights into how intrinsic protein disorder mediates regulatory processes and provide opportunities for designing drugs that target cancer-associated IDPs.