Novel monoclonal antibody therapies are increasing in number and clinical significance as their role in oncologic formularies expands. Anti-CD38 and anti-CD47/SIRPα agents commonly interfere with pretransfusion compatibility testing. Anti-CD38 interference is mitigated by dithiothreitol, which disrupts CD38 antigen on reagent red cells; however, this modification limits rule-out of all clinically significant antibodies. Several anti-CD47 agents are in clinical trials and demonstrate wide variability in pretransfusion testing interference. Modifications to pretransfusion testing can limit interference by anti-CD47 agents. Rapid dissemination of knowledge of these monoclonal antibody agents to the broader transfusion medicine community is paramount for continued patient transfusion safety.