Vernal keratoconjunctivitis (VKC) is a recurrent or chronic ocular allergic disease that affects mostly children and young adults living in warm climates worldwide. Understanding and treating VKC has been a challenge for ophthalmologists since the pathogenesis is unclear and anti-allergic therapy often unsuccessful. In this paper, the culmination of 11 years of research into the immunological characteristics of this disease in a group of 221 VKC patients will be presented. Cytological, biohumoral, immunohistological and molecular biological studies indicate that VKC is a Th2 lymphocyte-mediated disease. Mast cells, eosinophils and their mediators play major roles in the clinical manifestation of VKC. In addition to typical Th2-derived cytokines, IL-4, IL-5 and IL-13, other cytokines, chemokines, growth factors and enzymes are over-expressed in the conjunctiva of VKC patients. Furthermore, structural cells, such as epithelial cells and fibroblasts, are involved both in the inflammatory process and in the tissue remodeling phase, ultimately resulting in the formation of giant papillae. Interactions between specific (IgE- and Th2-mediated) and non-specific triggers and mechanisms may account for treatment failure. New insights into the pathogenesis of VKC should generate the means to better design the strategies for this complex disease.