It is of great importance to pinpoint specific residues or sites of a protein in biological contexts to enable desired mechanism of action for small molecules or to precisely control protein function. In this regard, acidic residues including aspartic acid (Asp) and glutamic acid (Glu) hold great potential due to their great prevalence and unique function. To unlock the largely untapped potential, great efforts have been made recently by synthetic chemists, chemical biologists and pharmacologists. Herein, we would like to highlight the remarkable progress and particularly introduce the electrophiles that exhibit reactivity to carboxylic acids, the light-induced reactivities to carboxylic acids and the genetically encoded noncanonical amino acids that allow protein manipulations at acidic residues. We also comment on certain unresolved challenges, hoping to draw more attention to this rapidly developing area.