DLBCL is increasingly being recognized as a heterogeneous disease with distinct molecular subtypes. This has challenged the rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) treatment paradigm in recent years, as several DLBCL subtypes have inferior survival after standard R-CHOP therapy. So how do you choose? In this review the authors conclude with proposed clinical management scenarios in which DA-R-EPOCH may be preferred, including some for patient populations in which the use of R-CHOP vs. DA-R-EPOCH is controversial.