The feasible region in which experimental optimization can be carried out is often irregular in shape, so that the performance of the usual symmetric experimental designs is disappointing. This is illustrated by the optimization of pH and solvent strength in HPLC. The definition of the feasible region is described. This region is searched with a set of uniformly spaced informative experiments determined with the Kennard and Stone algorithm, The optimization procedure is sequential, and the quality of each separation is judged by means of a multicriteria decision-making method. if none of the experiments leads to a chromatogram with an acceptable combination of optimization goals, then better experimental conditions are searched by following chromatographic expertise. The possibility of using D-optimal designs to model the chromatographic parameters over the feasible region is also discussed. As an example, pH and solvent strength of the mobile phase are optimized in the reversed-phase liquid chromatography separation of a mixture of four chlorophenols.