In Sjögren's syndrome, like in most other autoimmune diseases, the enigma 
leading to a pathogenic attack against self has not yet been solved. By 
definition, the disease must be mediated by specific immune reactions against 
endogenous tissues to qualify as an autoimmune disease. In Sjögren's syndrome 
the autoimmune response is directed against the exocrine glands, which, as 
histopathological hallmark of the disease, display persistent and progressive 
focal mononuclear cell infiltrates. Clinically, the disease in most patients is 
manifested by two severe symptoms: dryness of the mouth (xerostomia) and the 
eyes (keratoconjunctivitis sicca). A number of systemic features have also been 
described and the presence of autoantibodies against the ubiquitously expressed 
ribonucleoprotein particles Ro (Sjögren's-syndrome-related antigen A - SSA) and 
La (SSB) further underline the systemic nature of Sjögren's syndrome. The 
original explanatory concept for the pathogenesis of Sjögren's syndrome proposed 
a specific, self-perpetuating, immune mediated loss of acinar and ductal cells 
as the principal cause of salivary gland hypofunction. Although straightforward 
and plausible, the hypothesis, however, falls short of accommodating several 
Sjögren's syndrome-related phenomena and experimental findings. Consequently, 
researchers considered immune-mediated salivary gland dysfunction prior to 
glandular destruction and atrophy as potential molecular mechanisms underlying 
the symptoms of dryness in Sjögren's syndrome. Accordingly, apoptosis, fibrosis 
and atrophy of the salivary glands would represent consequences of salivary 
gland hypofunction. The emergence of advanced bio-analytical platforms further 
enabled the identification of potential biomarkers with the intent to improve 
Sjögren's syndrome diagnosis, promote the development of prognostic tools for 
Sjögren's syndrome and the long-term goal to identify possible processes for 
therapeutic treatment interventions. In addition, such approaches allowed us to 
glimpse at the apparent complexity of Sjögren's syndrome.