T-cell lymphomas (TCL) are characterized by poor response to chemotherapy and generally poor outcome. While molecular profiling has identified distinct biological subsets and therapeutic targets in B-cell lymphomas, the molecular characterization of TCL has been slower. Surface markers expressed on malignant T-cells, such as CD2, CD3, CD4, CD25, and CD52 were the first TCL-specific therapeutic targets to be discovered. However, the presence of these receptors on normal T-cells means that monoclonal antibody (mAb)- or immunotoxin (IT)-based therapy in TCL inevitably results in variable degrees of immunosuppression. Thus, although some mAbs/IT have significant activity in selected subsets of TCL, more specific agents that target signaling pathways preferentially activated in malignant T-cells are needed. One such novel class of agents is represented by the histone deacetylase (HDAC) inhibitors. These molecules selectively induce apoptosis in a variety of transformed cells, including malignant T-cells, both in vitro and in vivo. Several HDAC inhibitors have been studied in TCL with promising results, and have recently been approved for clinical use. Immunomodulatory drugs, such as interferons and Toll Receptor (TLR) agonists have significant clinical activity in TCL, and are particularly important in the treatment of primary cutaneous subtypes (CTCL). Although most classical cytotoxic drugs have limited efficacy against TCL, agents that inhibit purine and pyrimidine metabolism, known as nucleoside analogues, and novel antifolate drugs, such as pralatrexate, are highly active in TCL. With improved molecular profiling of TCL novel pharmacological agents with activity in TCL are now being discovered at an increasingly rapid pace. Clinical trials are in progress and these agents are being integrated in combination therapies for TCL, both in the relapsed/refractory setting as well as front line.