We have performed a combined experimental and computational study of the folding of a 21-residue alpha-helix-forming heteropeptide (WH21). Temperature jump kinetics with improved dynamic range at several temperatures revealed non-exponential relaxation that could be well described with two time constants of 20 and 300 ns at 298 K. In the computational part, we performed multi-microsecond molecular dynamics simulations of WH21 in explicit water, using the AMBER03 and OPLS/AA potentials. The simulations were in good agreement with available experimental data on helix content and relaxation times. On the basis of 70 individual transitions, we identified the main pathways of helix unfolding. Three paths were found in both force fields, with unfolding progressing through (1) N-terminus, C-terminus, and center; (2) C-terminus, N-terminus, and center; and (3) C-terminus, center, and N-terminus. An additional fourth path starting in the central region and expanding to the termini was detected only with AMBER03. Intermediate structures sampled along the pathway included a central helix with frayed termini, an off-center helix, and a helical hairpin. The simulations suggest that the short relaxation should be assigned to partly cooperative fluctuations of several neighboring hydrogen bonds. Overall, by a combination of ultrafast kinetic measurements and detailed microscopic description through comprehensive molecular dynamics, we have obtained important new insights into the helix folding process.