Cysteine side-chains can exist in distinct oxidation states depending on pH and redox potential of the environment. Therefore, cysteine reactivity has an important yet complex role as a regulatory element of protein structure and function. While some features have been extensively studied, the interplay between electrostatics and redox potential, and its effects on molecular structure remain difficult areas of research for computational methods. We present a large-scale, comprehensive analysis of the role of cysteine reactivity as a regulatory factor in proteins, while focusing simultaneously on its side-chain’s pKa and redox potential as key determinants of the resulting oxidation state. An exhaustive review of current computational approaches suggests underdeveloped areas of research and ideas to improve methodology to study cysteine reactivity through molecular simulations.