Vorinostat is the very first approved inhibitor of histone deacetylase, widely used in many countries for the treatment of primary/ persistent cutaneous T cell lymphoma (CTCL). However, problems associated with intrinsic and acquired resistance to vorinostat present a significant challenge to therapy. Here, we present our in vitro findings on the development and characterization of acquired resistance to vorinostat in a CTCL line HuT78 (HuT78VR). Employing an integrated transcriptomics and proteomics approach, we identified molecular signatures of vorinostat resistance in HuT78VR. We noted defective apoptosis, enhanced drug-efflux ability, upregulation of metastasis-related genes and mitogen-activated protein kinase signaling, increased cellular invasiveness, and downregulation of caspase 3 and phosphorylated forms of STAT3 in HuT78VR cells. HuT78VR cells gained cross-resistance to commonly used inhibitors of histone deacetylase and topoisomerase. Intriguingly, HuT78VR cells remained sensitive to inhibitors of STAT3, Janus-associated kinase, and extracellular receptor kinase, suggesting their pertinence in the management of vorinostat resistant CTCL.