Ionization and lipophilicity may vary with the environment. Therefore, in this study we provide some insight in the performances of different experimental techniques (potentiometry, UV-vis, shake-flask and chromatography) to determine ionization and lipophilicity in more nonpolar systems than those commonly used in drug discovery. To this purpose a pool of 11 compounds of pharmaceutical interest was firstly submitted to a few experimental techniques to measure pK<sub>a</sub> in water, water/acetonitrile mixtures and pure acetonitrile. Then we measured logP/logD with shake-flask and potentiometry in octanol/water and toluene/water and also determined a chromatographic lipophilicity index (log k'80 PLRP-S) in a nonpolar system. Results show that ionization decreases for both acids and bases in a coherent, significant but not dramatical extent when water is present in the system, but the picture is completely different in pure acetonitrile. Lipophilicity may vary or not with the environment according to the chemical structure of the investigated compounds as also revealed by electrostatic potential maps. Since the internal core of cell membranes is largely nonpolar, our results support the need of extending the pool of physicochemical descriptors to be determined in the various stages of drug discovery programs and indicate some experimental strategies for their determination.