Over the past 20 years it has become clear that dry eye syndrome (DES) or keratoconjunctivitis sicca (KCS) is a complex multifactorial disease characterized by an immune and inflammatory process that affects the lacrimal glands and ocular surface. In this paradigm, inflammation is seen as both the cause and consequence of conjunctival and corneal cell damage. In this chapter, we identify the unique characteristics of the lacrimal gland, the role of epithelial cells, regulatory T cells, and cytokines in maintaining ocular surface homeostasis and tear secretion function. We analyze the factors inducing loss of the lacrimal gland homeostasis and its consequences, and in so doing hope to provide a picture of the role of the immune system in the pathophysiology of KCS and useful information to help understand the complexity of DES.