This article provides a comprehensive classification of proteoglycan gene families and their respective protein cores, based on three criteria: cellular and subcellular location, overall gene/protein homology, and the presence of specific protein modules within their cores. These criteria have been used to design four major classes of proteoglycans: intracellular, cell-surface, pericellular, and extracellular. The proposed nomenclature includes 43 distinct proteoglycan-encoding genes and many alternatively spliced variants. The biological functions of these four proteoglycan families are critically assessed in development, cancer, angiogenesis, and various acquired and genetic diseases where their expression is aberrant. The article also discusses the modular design of proteoglycan cores, where each module represents a functional domain that affects cell-matrix dynamics. Specific examples of proteoglycans, such as serglycin, syndecans, CSPG4/NG2, betaglycan, phosphacan, glypicans, perlecan, agrin, collagens XVIII and XV, and hyalectans, are detailed, highlighting their unique structures, functions, and roles in various biological processes.This article provides a comprehensive classification of proteoglycan gene families and their respective protein cores, based on three criteria: cellular and subcellular location, overall gene/protein homology, and the presence of specific protein modules within their cores. These criteria have been used to design four major classes of proteoglycans: intracellular, cell-surface, pericellular, and extracellular. The proposed nomenclature includes 43 distinct proteoglycan-encoding genes and many alternatively spliced variants. The biological functions of these four proteoglycan families are critically assessed in development, cancer, angiogenesis, and various acquired and genetic diseases where their expression is aberrant. The article also discusses the modular design of proteoglycan cores, where each module represents a functional domain that affects cell-matrix dynamics. Specific examples of proteoglycans, such as serglycin, syndecans, CSPG4/NG2, betaglycan, phosphacan, glypicans, perlecan, agrin, collagens XVIII and XV, and hyalectans, are detailed, highlighting their unique structures, functions, and roles in various biological processes.