Hemoglobin-based oxygen carriers (HBOC) are being developed to provide the oxygen necessary in clinical situations when whole blood is not available. The safety and effectiveness of each HBOC must be determined before clinical approval. In the past several years animal studies have been conducted with zero-linked polymers to evaluate their effectiveness at delivering oxygen in vivo. Studies have addressed issues associated with interstitial extravasation, cerebral ischemia and blood flow, resuscitation, and coagulation interactions. Several of the investigations reviewed are based on early preparations of zero-linked polymerized bovine hemoglobins (ZL-HbBv), which contained a wide range of high-molecular-weight polymers. Recent studies using the Oxyvita product OxyVita Hb, which contains a more homogenous population (97%) of large-molecular-weight species (~17 MDa), are also included in this review.