Sezary syndrome (SS) is a rare form of cutaneous T-cell lymphoma characterized by erythroderma and the presence of Sezary cells in the skin, lymph nodes, and peripheral blood. Over the past few decades, cytogenetic and molecular cytogenetic findings have revealed many genetic alterations in patients with SS. The most frequent genetic lesions include monosomy 10, losses of 10q and 17p, gains of 8q24 and 17q, and diverse structural alterations involving these regions. Expression patterns in regions of genomic imbalance show that a large number of genes in SS are deregulated, and this might have a causative role in oncogenesis. Overall, chromosomal instability is characteristic of this lymphoma and related to a poor prognosis, but no specific abnormalities that may be directly involved in development of the disease have yet been found.