Sjögren's syndrome (SjS) is a systemic autoimmune disease in which an immunological attack against the salivary and lacrimal glands results, respectively, in severe dry mouth and dry eye diseases. Although a CD4⁺ T lymphocyte population is an integral component in the pathogenesis of SjS, recent studies have focused on the importance the B lymphocyte plays in both the pre-clinical and clinical phases of the disease process. To understand the molecular and cellular mechanisms involved in SjS, numerous mouse models that mimic major clinical manifestations of the human disease have been developed. Studies have begun to define the genetics, the nature of the autoimmune response towards the salivary and lacrimal glands, as well as the possible mechanisms for effecting glandular dysfunction, thereby establishing insights to new intervention therapies. Not surprising, the B cell is taking center stage. Here, we present an in-depth discussion of how B cell populations may be involved in orchestrating or determining exocrine gland dysfunction.