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Type IV of hypersensitivity reaction is usually manifested in the skin in different clinical pattern. According to traditional Gell and Coombs classification, the mechanism of IV type of allergic reaction has been associated with contact allergy with the activity of lymphocytes Th1 secreting interferon gamma. Now, this vision seems to be too simplified. In the last years there were publications, which can throw a new light on these complicated mechanisms leading to the development of the type IV of allergy, especially to drugs, nickel and other haptens and also can explain the differentiation of clinical pattern in respective patients. The skin symptoms in type IV of hypersensitivity are triggered by activation of specific T-cell CD4+ and CD8+. Immunohistochemical and functional analysis of reactive T-cell has shown that the delayed hypersensitivity reaction depends on the secreted cytokines. For example maculo-papular exanthema may be either triggered by Th1 or Th2 in nature and cytokines interferon gamma, tumor necrosis factor alfa or interleukin-4, 5 and 13. Bullous reactions (i.e. Stevens-Johnsons Syndrome or toxic epidermal necrolysis) are characterized by widespread keratinocyte apoptosis, a consequence of high CD8+ T-cell involvement and the molecular cytotoxicity of Fas, perforin and granzyme B. Pustular exanthema reactions are stimulated via the T-cell release of 11-8 and granulocyte-monocyte colony-stimulatig factor (GM-CSF). For the better understanding of these inflammatory cascades deleted type IV of hypersensitivity reactions have been re-classified into four main subtypes: 1. IVa with Th1 and monocyte directed and cytokines: IFNgamma, IL-1, IL-2, 2. IVb with Th2 and eosinophils directed and cytokines: L-5, IL-4, IL-13, 3. IVc with T CD8+ directed and cytokines: perforin, granzyme B, Fas Ligand, 4. IVd with T CD4+, CD8+ and neutrophil directed and cytokines: IL8, GM-CSF. Clinically delayed hypersensitivity eruptions are often an overlap of cytokine pathways, with one preferential reaction dominating the final picture. Type IVa and IVc play a role inthe mechanism of contact dermatitis, however type IV b in chronic asthma, chronic allergic rhinitis and maculo-papular exanthema with eosinophilia, type IV c in bullous reactions (i.e. Stevens-Johnsons Syndrome or toxic epidermal necrolysis), so type IV d in pustular exanthema reactions (i.g. AGEP - Acute Generalized Exanthematosus Pustule, Behcet disease). This different clinical pattern of allergic disease mainly including drug allergy to nickel and other haptens as well as chronic asthma and allergic rhinitis may be explained by above mechanisms. The study of different mechanisms of four subtypes of type IVof allergic reaction may be helpful in the differential diagnostics and in the treatment of allergic diseases.