Availability of a suite of biomarkers for early detection, stratification into distinct subtypes, and monitoring progression or response to therapy promises significant improvements in clinical outcomes for cancer patients. However, despite the recent progress in proteomics technologies based on mass spectrometry (MS), discovery of novel clinical assessment tools has been slow. This is, partly due to the inherent difficulties in working with blood as the biospecimen for candidate discovery. A better understanding of the limitations of blood for comparative protein profiling and a better appreciation of the advantages of cancer tissue or cancer cell secretomes have the potential to greatly enhance the progress.