To attempt description of the set of mRNA and protein (sialome) expressed in the salivary glands of the tick Ixodes scapularis, we randomly sequenced 735 clones of a full-length salivary gland cDNA library of this arthropod and performed Edman degradation of protein bands from salivary gland homogenates (SGH) and saliva separated by SDS-PAGE. The sequences were grouped into 410 clusters, of which 383 are not associated with known I. scapularis sequences. 15- and 17-protein bands from PAGE yielded amino-terminal information on the saliva and salivary gland gels, respectively. We attributed 19 of these sequences to translation products of the cDNA library. Full-length sequences were obtained for 87 clones. Among these protein sequences are several protease inhibitors of distinct classes, metalloproteases, novel proteins with histamine-binding domains, and several peptide families of unknown function displaying different conserved cysteine residues, many of which contain single Kunitz domains. This work provides information into the diversity of messages expressed in the salivary glands of I. scapularis, describes novel sequences that may be responsible for known biological activites, indicates further biological activities that may be present in I. scapularis saliva and identifies novel vaccine targets that may be used in Lyme disease prevention.