Serum and plasma are composed of highly complex protein/peptide mixtures resulting from the systemic monitoring of every biological process in a living organism. Some of these sentinel changes are extremely short-lived while others produce more stable by-products. In addition, since biological events occur simultaneously and with overlapping physiological demands, separating the desired ones from "background" changes is an exceptional challenge. In this review, we outline a definition of the "low molecular weight proteome" as a valuable subcomponent of the blood proteome. We make a case that this derivative proteome is as information rich and equally complex as the parent proteome. We discuss some of the technical challenges in the analysis of the low molecular weight proteome with an emphasis on MS-based analytical approaches. With specific example of several reported methodologies we attempt to frame the current state-of-the-art in study design as a guide to future efforts.