The translation of blood-based proteomics into healthcare is no longer constrained primarily by technological limitations, but by unresolved challenges in standardization, validation, and implementation. In this Commentary, we identify four structural bottlenecks at the current translational inflection point that limit the opportunities for the adoption of multi-protein blood biomarkers in routine clinical care: lack of harmonized reference frameworks, uncertainty around fit-for-purpose biological resolution, complexity in validating multi-analyte and algorithm-based tests, and misalignment between the design of discovery workflows and clinical requirements. We argue that progress will depend on shifting from exploratory profiling toward decision-oriented proteome analytics, with early alignment across academic, regulatory, clinical, and technical domains. Establishing coherent validation pathways for clinically actionable use cases will be essential to enable reliable integration of proteomics into healthcare.