The non-obese diabetic (NOD) mouse is now recognized as an appropriate model to study autoimmune exocrinopathy prevalent in human Sjögren's syndrome patients. With increasing age, NOD mice undergo histopathological changes similar to human Sjögren's syndrome patients, but more importantly, exhibit the same clinical manifestation of declining exocrine tissue secretory function. Studies with the immunodeficient NOD-scid mouse have provided evidence for the temporal loss in the expression of several major salivary proteins and a decreased presence of acinar cells in salivary tissues. The diminished presence of acinar cells is accompanied by an increase in the enzymes associated with apoptosis in the absence of T- and B-lymphocytes. Despite these alterations, NOD-scid mice, unlike NOD mice, do not lose secretory function. Recent analyses of a second congenic NOD strain, the NOD.Igmnull, which lacks B-lymphocytes, indicate the histological presence of a T-cell infiltrate of the exocrine glands, increased caspace activity and induction of the biochemical alterations in protein expression observed in NOD and NOD-scid mice. NOD.Igmnull mice also do not lose secretory function, but can be manipulated to generate a reduced secretory response following the infusion of IgG fractions from autoimmune NOD mice or Sjögren's syndrome patients. These observations, in the absence of components of the adaptive arm of the immune system, have given rise to the concept that autoimmune exocrinopathy develops in two phases. The initial phase is lymphocyte independent and occurs as a consequence of an innate error in exocrine tissue homeostasis or differentiated function. The subsequent tissue specific immunological attack, generated in part by B-cell autoantibodies, is responsible for the loss of secretory function. Our preliminary observations in both NOD mice and Sjögren's syndrome patients is that antibody directed against the cell surface muscarinic/cholinergic receptors appears to play an important part in the onset of clinical disease.