This comprehensive review explores the use of chiral stationary phases (CSPs) in single-column simultaneous chiral-achiral high-performance liquid chromatography (HPLC) separation methods. CSPs, traditionally used for enantioselective drug analysis, have evolved to exhibit notable chemoselective properties, leading to the development of methodologies that enable simultaneous enantio- and chemoselective separations using a single CSP-based column. The review focuses on four major CSP types: cyclodextrin-, glycopeptide antibiotic-, protein-, and polysaccharide-based CSPs, and discusses their diverse applications in various chromatographic modes, including normal phase (NP), reverse phase (RP), and polar organic (PO). It critically examines method development, emphasizing the additional chemoselective separation mechanisms of CSPs and explores possibilities for method optimization and future perspectives. Despite challenges in understanding retention mechanisms, the review highlights promising trends and anticipates an increasing number of simultaneous enantio- and chemoselective methods in pharmaceutical analyses, pharmacokinetic studies, and environmental sample determinations.This comprehensive review explores the use of chiral stationary phases (CSPs) in single-column simultaneous chiral-achiral high-performance liquid chromatography (HPLC) separation methods. CSPs, traditionally used for enantioselective drug analysis, have evolved to exhibit notable chemoselective properties, leading to the development of methodologies that enable simultaneous enantio- and chemoselective separations using a single CSP-based column. The review focuses on four major CSP types: cyclodextrin-, glycopeptide antibiotic-, protein-, and polysaccharide-based CSPs, and discusses their diverse applications in various chromatographic modes, including normal phase (NP), reverse phase (RP), and polar organic (PO). It critically examines method development, emphasizing the additional chemoselective separation mechanisms of CSPs and explores possibilities for method optimization and future perspectives. Despite challenges in understanding retention mechanisms, the review highlights promising trends and anticipates an increasing number of simultaneous enantio- and chemoselective methods in pharmaceutical analyses, pharmacokinetic studies, and environmental sample determinations.