It has been shown that the active acidic and proline-rich C-terminal activation domain of human c-Fos is structurally disordered and has the properties of an unfolded protein. It was found that disorder was not due to the deletion of a sequence necessary for structure. Structural disorder has also been found with the acidic activation domains from VP16, κB, and p53. Results for c-Fos and for the p53 proline-rich activation domain have indicated that proline-rich activation domains can exhibit structural disorder. Proposed mechanistic advantages of these disordered protein domains include increased binding specificity at the expense of thermodynamic stability, regulation of proteolysis, and the ability to recognize a range of different proteins. The C-terminal activation domain contains a number of phosphorylation sites that moderate Fos activity. The conformational freedom of the structurally disordered C-terminal activation domain contributes to the functional diversity of c-Fos by allowing the formation of numerous protein complexes (with transcription factors and with regulatory kinases).