Lymphoma is the most common hematologic neoplasm of dogs. Although the order of drug administration and duration of the maintenance portion of the protocol vary considerably, most oncologists agree that a doxorubicin-based (eg, CHOP) combination chemotherapy protocol provides the longest period of disease control and overall survival. The use of a prolonged maintenance phase is no longer recommended, but consolidation therapy may prove to be of benefit. Further, combination of chemotherapy with half- or whole-body radiation therapy or even bone marrow transplant is advocated by some institutions. The goal of this article is to summarize the current literature regarding chemotherapy for dogs with high-grade lymphoma and provide recommendations for therapy in a variety of different scenarios.