Psoriasis is a chronic disease, the pathogenesis of which involves many parts of the immune system. Disorders of innate and adaptive immune responses in the skin are the base for the occurrence and maintenance of “cytokine-regulated” inflammation, resulting in uncontrolled keratinocyte proliferation and reduced differentiation. The cytokine profile and molecular immune links involved at different stages of psoriasis are described. The most effective methods of topical treatment are discussed. Experience in the use of betamethasone dipropionate and calcipotriol combination in the therapy of psoriasis of smooth skin and “problem” localization is presented. It is noted that each component provides anti-inflammatory and immunomodulatory effects, synergistically acting when used together and providing greater efficacy of therapy than each of the active substances alone. The synergism is confirmed by cytokine profile analysis: the production of cytokines and chemokines key for the psoriasis pathogenesis, IL-6, 8, 17, 22, 23, TNF-α by keratinocytes and resident immune skin cells decreased significantly in patients receiving the combined therapy versus monotherapy, while the differentiation of regulatory T-cells important for immune response control (T-reg cells bearing FoxP3 marker) and their production of anti-inflammatory cytokine IL-10, in contrast, is increased. The combination of the two components also improves the safety profile as the biological effects of calcipotriol offset the atrophogenic effects of the steroid.