The plasma proteome offers a wealth of opportunity to develop protein-based assays for diagnostic, prognostic and predictive biomarkers. Nonetheless, the unique properties of plasma, with its high dynamic range of protein concentrations and the vast complexity of protein species, present considerable analytical challenges. The continuing maturation of proteomic technologies, in particular biological MS instrumentation and immunoaffinity sample preparation strategies, is driving progress in the field. Selected reaction monitoring (SRM)-MS of peptides derived from plasma proteins is one such development that facilitates high-fidelity selection and quantitation with only minimal prior sample enrichment, while coupling targeted immunoaffinity enrichment prior to SRM-MS further enhances detection of less-abundant plasma proteins present in the subnanogram per millilitre concentration. This article reviews recent progress in the bioanalysis of plasma proteins driven by SRM-MS.