Allergic and autoimmune disorders share significant functional overlap in the biologic pathways responsible for the activation of signal transduction events leading to production of numerous proinflammatory factors involved in disease initiation and progression. Given the reciprocal connections in these mechanistic pathways, it would be advantageous to target strategic master regulators with novel therapeutics to treat allergic and autoimmune diseases. One such crucial regulator is spleen tyrosine kinase (SYK), a member of the cytoplasmic protein tyrosine kinase (PTK) family. Geahlen et al. initially reported SYK as a proteolytically derived fragment (p40) from a parent p72 protein extracted from bovine thymus.1,2 The isolated p40 protein was found to be catalytically active, possessing an adenosine 5′-triphosphate (ATP) binding site, and capable of intramolecular autophosphorylation of tyrosine residues.1,2 Further studies have led to the observation that antibodies to p40 concomitantly showed cross-reactivity with a 72 kDa protein-tyrosine kinase from the spleen and thymus.1,2 Yamamura et al. corroborated the earlier work, employing immunoblot analysis using anticytosolic protein-tyrosine kinase-40 antibody made for the N-terminal portion of the 40 kDa kinase, and identified a 72 kDa protein, which is now known as the SYK protein.3,4 Application of a partial sequence oligonucleotide probe for the 40 kDa kinase led to a clone comprising the complete coding sequence for the 40 kDa kinase; the clone was made up of 628 amino acids with a molecular weight of 71 618 Da and corresponded to acidophilic SYK kinase.5−8 Subsequent to its initial discovery, SYK has garnered substantial attention because of its importance as a key signal transduction regulator through antigen and Fc receptors in hematopoietic cells.9−11 The validity of SYK as a target for therapeutic intervention has progressed over the past 15 years, and SYK has recently entered the mainstream of potential pharmaceutical targets with a number of inhibitor classes being reported in the literature.12−17 The true potential as a validated target for inhibition by small molecules has also been investigated in the past few years, with advanced clinical trial data only emerging during this period of time (vide infra).