Display omitted •A first of its kind review on use of experimental designs in HPLC method development and validation.•Deals with recent advances in mathematical modeling, screening and optimization designs.•Discusses various applications of chemometry in sample preparation, dissolution studies, stability-indicating assays.•Demonstrates complex multi component UPLC and LC–MS separations with improved reliability.•Describes the quality by design paradigm and the six sigma practices as quality indicators. Chemometric approaches have been increasingly viewed as precious complements to high performance liquid chromatographic practices, since a large number of variables can be simultaneously controlled to achieve the desired separations. Moreover, their applications may efficiently identify and optimize the significant factors to accomplish competent results through limited experimental trials. The present manuscript discusses usefulness of various chemometric approaches in high and ultra performance liquid chromatography for (i) methods development from dissolution studies and sample preparation to detection, considering the progressive substitution of traditional detectors with tandem mass spectrometry instruments and the importance of stability indicating assays (ii) method validation through screening and optimization designs. Choice of appropriate types of experimental designs so as to either screen the most influential factors or optimize the selected factors’ combination and the mathematical models in chemometry have been briefly recalled and the advantages of chemometric approaches have been emphasized. The evolution of the design of experiments to the Quality by Design paradigm for method development has been reviewed and the Six Sigma practice as a quality indicator in chromatography has been explained. Chemometric applications and various strategies in chromatographic separations have been described.