The diagnosis and classification of leukemia requires the integration of clinical features and light microscopic findings with the results of cytochemical, immunological (flow cytometry and/or immunohistochemistry), and molecular studies [1]. Immunophenotypic and genotypic technologies are commonly applied to peripheral blood (PB) and bone marrow (BM) specimens in the initial work-up and management of patients with leukemia. It is critical to definitively characterize the disease, due to differences in treatment regimens and prognosis among leukemia subtypes [1]. Skin lesions that may arise in patients with leukemia can be divided into two groups: (a) “leukemids” or nonspecific reactions, in which inflammatory lesions contain no neoplastic cells; and (b) leukemia cutis (LC) or specific lesions, in which leukemic cells (myeloid or lymphoid) infiltrate the skin [2, 3]. Commonly used terms for LC composed of myeloid blasts include chloroma, extramedullary myeloid sarcoma, granulocytic sarcoma, and monoblastic sarcoma [1, 3]. This chapter discusses some of the limitations of traditional methodologies, and potential applications of molecular technologies, in the diagnosis and follow-up of patients with LC.