Primary cutaneous T-cell lymphomas (CTCLs) are a heterogeneous group of non-Hodgkin's lymphomas characterized by skin infiltration of neoplastic T lymphocytes. Mycosis fungoides and its leukemic variant Sézary syndrome represent the most common CTCL subtypes. Current treatment for patients with mycosis fungoides involves topical and systemic therapies for the cutaneous manifestations. However, no therapy is curative and patients often progress to advanced extracutaneous CTCL with visceral organ complications or relapsed disease that is frequently refractory to most topical and aggressive systemic regimens. The emergence of novel targeted therapies such as biologic agents, histone deacetylase inhibitors, and purine nucleoside phosphorylase inhibitors offers promise for more effective and safer treatment strategies for refractory CTCLs.