Red blood cells (RBCs) are biconcave cells that circulate in the blood stream and provide oxygen to all tissues of the body. The number and lifespan of circulating RBCs are tightly regulated. “Old” RBCs undergo alterations that result in their recognition and removal from circulation by cells in the spleen (macrophages), whereas replacement RBCs are made in the bone marrow. In healthy animals, the exact nature of the alterations in RBCs and the mechanisms used to recognize and remove them are areas of active investigation. In immune-mediated hemolytic anemia (IMHA), RBCs are destroyed in excess of what the bone marrow can produce. The overall loss of RBC mass severely compromises the animal’s ability to deliver oxygen to the tissues. This disease can be severe and is often life-threatening with a reported mortality rate of 40% in dogs. Efforts to improve diagnosis and management of IMHA have long focused on the immunologic components of the disease. Recent data suggest that a closer look at changes in RBCs themselves is warranted. We propose a systematic approach to evaluation of RBC membrane alterations and signaling events hypothesized to contribute to their increased interaction with the immune system and removal from circulation. This study will rely on blood samples from canine patients with IMHA presented to the University of Wisconsin and has the potential to identify alterations in RBCs that may serve as diagnostic aids or therapeutic targets for this common and sometimes devastating disease in the future.