Cyclin-dependent kinase (Cdk) inhibitor p21^{Waf1/Cip1/Sdi1}, a multifunctional protein, has a major role as tumor suppressor, mediating G1/S arrest through inhibition of Cdks. Recent biological studies of Cyclin D1/Cdk4 have proposed that p21 C-terminal domain (p21^CT) plays a key role as a potent Cdk4 inhibitor. We report here solution structures of p21^CT for both the free and Cdk4-bound forms using 2D transferred NOE spectroscopy and dynamical simulated annealing calculations. Even though p21^CT peptide is very flexible in the free state, when it bound to Cdk4, the structure becomes well structured in the binding domain. Therefore we propose that p21^CT experiences an extensive conformational change upon Cdk4 binding. This structural change of p21^CT may suggest the molecular mechanism of p21 for specificity and inhibition mode to assemble different cyclin-Cdk complexes. Especially, our data suggests that the D¹⁴⁹FYHSKRR¹⁵⁶ region of p21 is critical for Cdk4 binding, indicating that the major driving force for complex originates from hydrophobic interaction between p21 and Cdk4.