Cutaneous T-cell lymphomas (CTCLs) are a diverse group of non-Hodgkin’s lymphomas that include mycosis fungoides and Sézary syndrome subtypes, affecting mainly the skin. Accurate diagnosis of CTCL variants and the stage of disease are both key factors for determining appropriate treatment strategies. Early-stage disease can often be effectively managed with skin-directed therapies. However, patients with more advanced disease benefit from systemic therapies, which are often associated with toxicities that degrade patients’ quality of life. Histone deacetylase (HDAC) inhibitors are a class of targeted agents that prevent deacetylation of histone/nonhistone proteins and affect a wide range of cellular functions regulated by HDACs. Vorinostat and romidepsin are HDAC inhibitors approved for the treatment of CTCL, whereas several others are under clinical evaluation for CTCL and other hematological malignancies. This article reviews important safety considerations with HDAC inhibitors. For dermatology and oncology nurses, identification and management of toxicities are critical to maintaining patient quality of life and ensuring optimal treatment outcomes. Quality nursing care is essential for the successful treatment of patients with CTCL. As newer and more complex options for CTCL are utilized, dermatology and oncology nurses play an important role in educating and managing patients and associated treatment-related toxicities.