Introduction: Mass spectrometry is starting to elucidate the extent of lipoprotein diversity. It is believed that HDL is comprised of proteins encoded by >100 genes and ~200 distinct lipid species in an undetermined number of combinations. Multiple proteoforms derived from a single gene contribute to particle complexity, confound proteome identification and makes differentiation of distinct subpopulations a challenge. Subtle proteoform variants can account for alterations in particle physicochemical properties and critical functions. Refining high-definition constituent identification within a structured atlas may reveal mechanism-based pathophysiology of a variety of diseases. Hypothesis: The ongoing identification of HDL constituents necessitates an effort to catalogue, categorize, map and relate entities in a framework that organizes this knowledge in a form of testable observations, explanations and predictions. Defining constituent interactions will advance knowledge and guide inquiry that enables HDL research, clinical diagnostics and subsequent therapeutic strategies. Methods: Informatic analysis of the literature produced an HDL proteome reference set. Proteome specific analysis of gene isoforms, proteolytic products, amino acid modifications and cSNPs were used to prepare a proteoform index. Theoretical tryptic peptide maps were generated and referenced to the PeptideAtlas and available published mass spec peptide lists. Results: Over 380 non-immunoglobulin proteins were identified in high-density lipoprotein fractions from human samples. A consensus-based scoring produced an “unofficial” list of 122 genes. UniProtKB was used to expand an index of potential proteoforms and derive a theoretical peptide mass library used to map empirically defined peptide spectral lists. Conclusions: Utilizing a reductionism model to HDL measurement has proven insufficient and undermines the application of Precision Medicine for CAD. Understanding the health benefits of HDL requires clinical diagnostics that captures particle diversity and population heterogeneity. Constructing a conceptual framework that unifies a constituent map is the initial step to resolving their relational context and functional consequences.