Collagen degradation is a physiological process necessary for regular tissue maintenance, but it is also a key player in the progression of several diseases, such as atherosclerosis, cancer, and rheumatoid arthritis. Despite its considerable medical and scientific importance, the molecular mechanism of collagen degradation has resisted explanation for more than three decades. In my talk, I will outline computational approaches, including both molecular dynamics and numerical simulations that we have employed to investigate how the conformational thermodynamics of collagen may play a role in its degradation. In combination with biochemical data, these simulations suggest that collagen readily samples disordered, partially unfolded states in the vicinity of the degradation site. This finding readily explains many of the paradoxical aspects of collagen degradation and also suggests new strategies for inhibiting disease-associated degradation.