Abstract-Sezary syndrome (SS) is a rare leukemic cutaneous T-cell lymphoma (CTCL) with an aggressive clinical course. It is characterized by erythroderma, generalized lymphadenopathy and neoplastic skin-homing CD4+ memory T cells (Sezary cells) in the skin, lymph nodes, and peripheral blood. Despite the availability of a number of active systemic therapeutic strategies, SS remains an incurable lymphoma. Recently, high throughput analyses have revealed a novel approach to identify the molecular process implicated in the development and tumorigenesis of SS, which is relevant to a pharmacological therapeutic strategy. The aim of this review is to describe some altered genes, starting from the main deregulated microRNAs discovered in SS.