Many chemical compounds with important biological and medicinal functions present acid-base equilibriums under physiological conditions. Most of these compounds behave as Brønsted acids (or bases) in aqueous solution and as such their acidity is commonly expressed as pKa. Obtaining reliable pKa values is a very challenging task both for experiments and computational approaches. In the article on page 3449, Annia Galano and coworkers compare the performances of a large set of strategies for accurate calculations of aqueous pKas of relatively large-sized molecules with protonated amino sites. The best identified approaches are then applied to the calculations of the pKas of different neurotransmitters.