Unmodified cell-free hemoglobin (Hb) is structurally unstable when transfused into the blood stream (Valeri et al., Artif Cells Blood Substit Immobil Biotechnol. 2000;28:451-475; Chan et al., Toxicol Pathol. 2000;28:635-642; Eike, Dissertation, 2005; Eike and Palmer, Biotechnol Prog. 2004;20:946-952). This review examines some of the latest chemical strategies used over the last 5 years to intra- and intermolecularly cross-link Hb, thereby stabilizing its quaternary structure. Therefore, this work will address the following aspects: (1) site-specific chemical modifications of Hb and (2) non-site-specific chemical modifications of Hb, including, but not limited to, PolyHeme(R), Hemopure(R), Oxyglobin(R), and SOD-Hb. Current strategies for synthesizing PEGylated Hb is outside the scope of this review and will not be discussed herein. For a more thorough review of PEGylated Hb, the reader is directed to the following works: Cabrales and Friedman, Transfus Alternatives in Transfus Med. 2007;9:281-293 and Winslow, Biochim Biophys Acta., 2008;1784(10):1382-1386.