The study presents an empirical framework for evaluating the quality and completeness of human protein-protein interaction (interactome) maps. It compares different methods for mapping interactions, including high-throughput yeast two-hybrid (HT-Y2H), co-affinity purification followed by mass spectrometry, and literature-curated interactions. The authors developed a framework to estimate key parameters such as screening completeness, assay sensitivity, sampling sensitivity, and precision. They used empirical data from positive and negative reference sets to assess the performance of different assays. The results indicate that HT-Y2H interactions are more precise than literature-curated interactions, suggesting that HT-Y2H is suitable for mapping a significant portion of the human interactome. The authors estimate that the human interactome contains approximately 130,000 binary interactions, most of which remain to be mapped. They also find that the precision of HT-Y2H datasets is higher than that of literature-curated interactions. The study highlights the importance of estimating the size and quality of interactome maps to guide future mapping efforts. The authors conclude that the human interactome is likely to contain around 74,000–200,000 binary interactions, excluding splice variant complexity. The study provides a quantitative roadmap for interactome mapping and emphasizes the need for unbiased, systematic, and cost-effective high-throughput approaches.The study presents an empirical framework for evaluating the quality and completeness of human protein-protein interaction (interactome) maps. It compares different methods for mapping interactions, including high-throughput yeast two-hybrid (HT-Y2H), co-affinity purification followed by mass spectrometry, and literature-curated interactions. The authors developed a framework to estimate key parameters such as screening completeness, assay sensitivity, sampling sensitivity, and precision. They used empirical data from positive and negative reference sets to assess the performance of different assays. The results indicate that HT-Y2H interactions are more precise than literature-curated interactions, suggesting that HT-Y2H is suitable for mapping a significant portion of the human interactome. The authors estimate that the human interactome contains approximately 130,000 binary interactions, most of which remain to be mapped. They also find that the precision of HT-Y2H datasets is higher than that of literature-curated interactions. The study highlights the importance of estimating the size and quality of interactome maps to guide future mapping efforts. The authors conclude that the human interactome is likely to contain around 74,000–200,000 binary interactions, excluding splice variant complexity. The study provides a quantitative roadmap for interactome mapping and emphasizes the need for unbiased, systematic, and cost-effective high-throughput approaches.