Renin is a pepsin-like aspartyl protease and an important drug target for the treatment of hypertension; despite three decades' research, its pH-dependent structure-function relationship remains poorly understood. Here, we employed continuous constant pH molecular dynamics (CpHMD) simulations to decipher the acid/base roles of renin's catalytic dyad and the conformational dynamics of the flap, which is a common structural feature among aspartyl proteases. The calculated pKa's suggest that catalytic Asp38 and Asp226 serve as the general base and acid, respectively, in agreement with experiment and supporting the hypothesis that renin's neutral optimum pH is due to the substrate-induced pKa shifts of the aspartic dyad. The CpHMD data confirmed our previous hypothesis that hydrogen bond formation is the major determinant of the dyad pKa order. Additionally, our simulations showed that renin's flap remains open regardless of pH, although a Tyr-inhibited state is occasionally formed above pH 5. These findings are discussed in comparison to the related aspartyl proteases, including β-secretases 1 and 2, cathepsin D, and plasmepsin II. Our work represents a first step toward a systematic understanding of the pH-dependent structure-dynamics-function relationships of pepsin-like aspartyl proteases that play important roles in biology and human disease states.