The most common T-cell lymphoma in the United States includes a heterogeneous mix of lymphomas that lack distinguishing characteristics and, until recently, remained clinically and molecularly “unspecified”. Improved understanding of T-cell lymphoma pathogenesis and the development of novel therapeutic strategies will be needed to address this challenge and improve outcomes for patients afflicted with these aggressive lymphomas. Many questions, including the “cell of origin”, the role of antigen-, costimulatory-, and cytokine-receptor signaling, and the contribution of myeloid-derived antigen-presenting cells in disease pathogenesis remain obscure. My laboratory uses complementary mouse models and primary T-cell lymphoma specimens (in ex vivo and patient-derived xenograft studies) to address these fundamental and clinically relevant questions. We are poised to clinically translate our laboratory-based findings into novel therapeutic strategies that we hope will improve outcomes for patients afflicted with these aggressive lymphomas.