There has been an exciting revolution in chemical biology to examine the proteome-wide reactivity and ligandability of cysteine residues using mass spectrometry proteomics. These studies have served as a starting point for identification of new ligandable protein targets and the development of covalent probes and drugs. Cysteine reactivity across the proteome is generally assessed by measuring labeling efficiency with a highly reactive iodoacetamide probe. Cysteine ligandability, on the other hand, is examined by treating the proteome with small-molecule covalent fragments bearing weaker electrophiles, like chloroacetamide or acrylamide, followed by treatment with an iodoacetamide probe. The loss of iodoacetamide labeling at specific cysteines reveals the selectivity profile of fragment electrophiles across the proteome. Cysteine ligandability screens have the potential to simultaneously identify target proteins and lead compounds for covalent probe development.