In this manuscript, we tackle the current controversies in the front-line treatment of systemic PTCL including (1) whether CNS prophylaxis should be administered; (2) whether CHOEP should be preferred over CHOP; (3) what role brentuximab vedotin should have; (4) whether stem cell transplant (SCT) consolidation should be used and whether autologous or allogeneic; (5) how should molecular subtypes (including DUSP22 or TP63-rearranged ALCL or GATA3 or TBX21 PTCL, NOS) impact therapeutic decisions; and (6) whether there is a role for targeted agents beyond brentuximab vedotin. The gene discussed is GATA3; the disease is anaplastic large cell lymphoma.