Recently, Liotta and colleagues pointed to the possibility that blood contains a vast amount of as yet unutilized and/or unidentified peptides that may have potential as diagnostic biomarkers (63). As indicated earlier, they believe that the tumor-host microenvironment should generate unique signatures in the blood microenvironment. A proposal was then made that the low-molecular-mass region of the blood proteome, which is a mixture of small intact proteins plus fragments of large proteins, represents all classes of proteins and is a treasure trove of diagnostic information largely ignored until now. Because small peptides can be effectively cleared by the kidney, the authors speculate that many of these low-molecular-mass proteins are bound to abundant serum proteins like albumin. This hypothesis needs to be tested experimentally. Experiments to validate this hypothesis should be straightforward. For example, many of these peptides can be characterized by using mass spectrometry. Then, these peptides, tagged with a stable isotope, can be used in recovery experiments to examine if they indeed bind to carrier proteins and what is their lifetime in the circulation. Furthermore, such experiments will reveal their abundance in the circulation and their origin (e.g. which are the parent proteins). Only when these experiments are done will the proposal of using these peptides for diagnostics gain more credence.