Peripheral T-cell lymphomas (PTCLs) account for about 12% of lymphoid tumours worldwide. Almost a half of them show such a morphologic and molecular variability as to hamper any further classification and to justify their inclusion in a waste-basket category termed “not otherwise specified (NOS)”. The latter corresponds to neoplasms with aggressive presentation, poor response to therapy and dismal prognosis. Conversely to B-cell lymphomas, PTCLs have so far been the object of a limited number of studies aiming to elucidate their pathobiology and identify novel pharmacologic approaches. Herewith, the authors revise the most recent contributions on the subject, based on the experience they gained in the extensive application of micro-array technologies. PTCLs/NOS are characterised by erratic expression of T-cell associated antigens, including CD4 and CD52, recently proposed as targets for ad hoc immunotherapies. They also show variable Ki-67 marking, rates > 80% heralding a worse prognosis. Gene expression profiling (GEP) studies reveal that PTCLs/NOS derive from activated T-lymphocytes, more often of the CD4+ type, and bear a signature composed of 155 genes and related products that play a pivotal role for cell signalling transduction, proliferation, apoptosis and matrix remodelling. This observation seems to pave the way to the usage of innovative drugs, such as tyrosine kinase and histone deacetylase inhibitors whose efficacy has been proven in PTCL primary cell cultures. GEP does also allow better distinction of PTCL/NOS from angioimmunoblastic T-cell lymphoma, the latter being characterised by follicular T-helper lymphocyte derivation and CXCL13, PD1 and VEGF expression.