H—NOX proteins are mutated to exhibit improved or optimal kinetic and thermodynamic properties for blood gas O2 delivery. The engineered H—NOX proteins comprise mutations that impart altered O2 or NO ligand-binding relative to the corresponding wild-type H—NOX domain, and are operative as physiologically compatible mammalian blood O2 gas carriers. The invention also provides pharmaceutical compositions, kits, and methods that use wild-type or mutant H—NOX proteins for the treatment of any condition for which delivery of O2 is beneficial.