This review discusses the use of chiral stationary phases (CSPs) in single-column simultaneous chiral–achiral high-performance liquid chromatography (HPLC) separation methods. CSPs are crucial for enantioselective drug analysis, but modern CSPs also exhibit chemoselective properties, enabling simultaneous enantio- and chemoselective separations. The review covers four major CSP types: cyclodextrin-, glycopeptide antibiotic-, protein-, and polysaccharide-based CSPs. It explores various chromatographic modes, including normal phase (NP), reverse phase (RP), and polar organic (PO), and discusses method development, optimization, and future perspectives. The review highlights the importance of CSPs in pharmaceutical analysis, pharmacokinetic studies, and environmental sample determinations. It also addresses challenges in understanding retention mechanisms in chemoselective separations and emphasizes the growing trend of simultaneous enantio- and chemoselective methods. The review provides an overview of various HPLC methods for the separation of chiral and achiral compounds, including examples of methods for drugs like verapamil, salmeterol, ketamine, and others. It discusses the application of CSPs in the analysis of metabolites, impurities, and enantiomers, and highlights the potential of CSPs in improving the efficiency and selectivity of HPLC methods. The review also addresses the importance of method validation, optimization, and the use of green methods in chiral analysis. Overall, the review aims to provide a comprehensive understanding of the current state of the art in chiral–achiral HPLC separations and to outline emerging trends and future directions in this field.This review discusses the use of chiral stationary phases (CSPs) in single-column simultaneous chiral–achiral high-performance liquid chromatography (HPLC) separation methods. CSPs are crucial for enantioselective drug analysis, but modern CSPs also exhibit chemoselective properties, enabling simultaneous enantio- and chemoselective separations. The review covers four major CSP types: cyclodextrin-, glycopeptide antibiotic-, protein-, and polysaccharide-based CSPs. It explores various chromatographic modes, including normal phase (NP), reverse phase (RP), and polar organic (PO), and discusses method development, optimization, and future perspectives. The review highlights the importance of CSPs in pharmaceutical analysis, pharmacokinetic studies, and environmental sample determinations. It also addresses challenges in understanding retention mechanisms in chemoselective separations and emphasizes the growing trend of simultaneous enantio- and chemoselective methods. The review provides an overview of various HPLC methods for the separation of chiral and achiral compounds, including examples of methods for drugs like verapamil, salmeterol, ketamine, and others. It discusses the application of CSPs in the analysis of metabolites, impurities, and enantiomers, and highlights the potential of CSPs in improving the efficiency and selectivity of HPLC methods. The review also addresses the importance of method validation, optimization, and the use of green methods in chiral analysis. Overall, the review aims to provide a comprehensive understanding of the current state of the art in chiral–achiral HPLC separations and to outline emerging trends and future directions in this field.