Patients presenting with autoimmune hemolytic anemias create inherent challenges to those tasked with providing compatible blood for transfusion therapy. These patients have developed autoantibodies against their own red cell surface antigens. Because these antigens are usually high-incidence, these patients will typically demonstrate panagglutination when their serum is exposed to most commercially procured screening red blood cells. This makes the identification of clinically significant alloantibodies difficult for laboratory personnel. Transfusion history, patient phenotype availability, and previous antibody records all impact the testing methods. The end goal is to identify clinically significant alloantibodies in order to provide antigen negative, compatible red blood cells, which reduces the risk of transfusion related reactions. It is imperative to understand the laboratory results and the techniques available that guide the investigative process.