The human plasma proteome holds the promise of a revolution in disease diagnosis and therapeutic monitoring, provided that major challenges in proteomics and related disciplines can be addressed. Plasma is not only the primary clinical specimen, but also represents the largest and deepest version of the human proteome present in any sample: in addition to the classical “plasma proteins”, it contains all tissue proteins (as leakage markers) plus very numerous distinct immunoglobulin sequences; and it has an extraordinary dynamic range, in that more than 10 orders of magnitude in concentration separate albumin and the rarest proteins now measured clinically. Although the restricted dynamic range of conventional proteomics has limited its contribution to the list of 289 proteins (tabulated here) that have been reported in plasma to date, very recent advances in multi-dimensional survey techniques promise at least double this number in the near future. Abundant scientific evidence, from proteomics and other disciplines, suggests that among these are proteins whose abundances and structures change in ways indicative of many, if not most, human diseases. Nevertheless, only a handful of proteins are currently used in routine clinical diagnosis, and the rate of introduction of new protein tests approved by the US FDA has paradoxically declined over the last decade to less than one new protein diagnostic marker per year. We speculate on the reasons behind this large discrepancy between the expectations arising from proteomics and the realities of clinical diagnostics, and suggest approaches by which protein-disease associations may be more effectively translated into diagnostic tools in the future.