The enantiomeric resolution of chiral drug molecules on HPLC chiral stationary phases (CSPs) is now a well-established technique; however, many methods still require achiral derivatization in order to enhance selectivity. Although considerable progress in direct resolution has been achieved, optimization of chiral resolution requires careful selection of CSP and mobile phase. We here report progress in the the direct resolution of a number of chiral drug substances. Chiral carboxylic acids, such as several of the non-steroidal anti-inflammatory agents, are resolved on CSPs which contain both pi-acidic and pi-basic aromatic groups, but not on phases with only one such interaction site; both normal and reverse phase conditions are effective. Chiral amines, including tertiary amines, are resolved on CSPs containing two chiral centers, or, when the chiral drug itself contains appropriate aromatic functionalities, on CSPs containing a complementary group. Acidic mobile-phase modifiers are often effective in promoting resolution of chiral amines, but the choice of acid can be crucial. These and other results are discussed from the standpoints of CSP selection and of analytical optimization.