A variety of bioactive proteins from medicinal leeches, like species of Hirudo, have been characterized and evaluated for their potential therapeutic biomedical properties. However, there has not previously been a comprehensive attempt to fully characterize the salivary transcriptome of a medicinal leech that would allow a clearer understanding of the suite of polypeptides employed by these sanguivorous annelids and provide insights regarding their evolutionary origins. An Expressed Sequence Tag (EST) library-based analysis of the salivary transcriptome of the North American medicinal leech, Macrobdella decora, reveals a complex cocktail of anticoagulants and other bioactive secreted proteins not previously known to exist in a single leech. Transcripts were identified that correspond to each of saratin, bdellin, destabilase, hirudin, decorsin, endoglucoronidase, antistatin, and eglin, as well as to other previously uncharacterized predicted serine protease inhibitors, lectoxin-like c-type lectins, ficolin, disintegrins and histidine-rich proteins. This work provides a lens into the richness of bioactive polypeptides that are associated with sanguivory. In the context of a well-characterized molecular phylogeny of leeches, the results allow for preliminary evaluation of the relative evolutionary origins and historical conservation of leech salivary components. The goal of identifying evolutionarily significant residues associated with biomedically significant phenomena implies continued insights from a broader sampling of blood-feeding leech salivary transcriptomes.