Intrinsically disordered proteins (IDPs) play a crucial role in cellular signaling and regulation, often interacting with multiple targets. Recent advances highlight the coupling of folding and binding in IDPs, where short motifs within disordered sequences fold upon binding. Techniques like NMR, SAXS, and single-molecule fluorescence provide insights into the conformational ensembles and dynamics of IDPs. The pKID domain of CREB exemplifies an induced folding mechanism, where binding to KIX induces helical structure formation. Coarse-grained simulations support this model, showing that folding occurs after binding and involves a partially folded intermediate. Similar mechanisms are observed in other IDPs, such as the CBD domain of WASP and the transactivation domains of c-Myc, Gal4, and VP16. Phosphorylation modulates IDP behavior, influencing conformational preferences and binding affinity. For example, phosphorylation of pKID enhances its binding to KIX through enthalpic effects. Disordered regions can also function as allosteric effectors, fine-tuning signaling responses. The Arf-Hdm2 interaction illustrates a novel mechanism where disordered domains fold synergistically to form amyloid-like structures. Kinetic studies reveal that IDPs can exhibit a wide range of binding rates, from diffusion-limited to slower processes. Cooperative binding is common, with IDPs forming ternary complexes through multiple interactions. The CFTR regulatory region interacts with NBD1 via transient helical motifs, demonstrating dynamic binding. In vivo, IDPs may remain disordered despite binding, as seen in Smad2-Smad anchor interactions. The PDEγ γ-subunit remains disordered in cells, though it includes a loosely folded state. IDPs are susceptible to proteolysis, but many are protected by complexation with other molecules. Chaperones do not preferentially bind IDPs, suggesting their intrinsic nature. Overall, IDPs are structurally flexible, with binding and folding mechanisms varying widely. Structural and computational studies continue to elucidate their roles in cellular processes, emphasizing the importance of disorder in protein function and signaling.Intrinsically disordered proteins (IDPs) play a crucial role in cellular signaling and regulation, often interacting with multiple targets. Recent advances highlight the coupling of folding and binding in IDPs, where short motifs within disordered sequences fold upon binding. Techniques like NMR, SAXS, and single-molecule fluorescence provide insights into the conformational ensembles and dynamics of IDPs. The pKID domain of CREB exemplifies an induced folding mechanism, where binding to KIX induces helical structure formation. Coarse-grained simulations support this model, showing that folding occurs after binding and involves a partially folded intermediate. Similar mechanisms are observed in other IDPs, such as the CBD domain of WASP and the transactivation domains of c-Myc, Gal4, and VP16. Phosphorylation modulates IDP behavior, influencing conformational preferences and binding affinity. For example, phosphorylation of pKID enhances its binding to KIX through enthalpic effects. Disordered regions can also function as allosteric effectors, fine-tuning signaling responses. The Arf-Hdm2 interaction illustrates a novel mechanism where disordered domains fold synergistically to form amyloid-like structures. Kinetic studies reveal that IDPs can exhibit a wide range of binding rates, from diffusion-limited to slower processes. Cooperative binding is common, with IDPs forming ternary complexes through multiple interactions. The CFTR regulatory region interacts with NBD1 via transient helical motifs, demonstrating dynamic binding. In vivo, IDPs may remain disordered despite binding, as seen in Smad2-Smad anchor interactions. The PDEγ γ-subunit remains disordered in cells, though it includes a loosely folded state. IDPs are susceptible to proteolysis, but many are protected by complexation with other molecules. Chaperones do not preferentially bind IDPs, suggesting their intrinsic nature. Overall, IDPs are structurally flexible, with binding and folding mechanisms varying widely. Structural and computational studies continue to elucidate their roles in cellular processes, emphasizing the importance of disorder in protein function and signaling.