Avian influenza viruses (AIV) have been reported to cause infections in humans following avian-to-human transmission resulting in a wide range of clinical outcomes. A(H5N1) and A(H7N9) infections, that constitute the majority of human AIV cases, are responsible for severe infections leading to high mortality. The neuraminidase (NA) inhibitor oseltamivir is expected to play a major role for the control of AIV infections in humans. However, the emergence of resistance may compromise the impact of antiviral therapy. The objective of this manuscript is to review human cases of A(H5N1) and A(H7N9) infections for which mutations of oseltamivir resistance were detected. NA mutations rapidly occurred in a subtype-specific manner with H274Y and N294S substitutions predominating in A(H5N1) cases and the R292K substitution in A(H7N9) cases. Serious clinical outcomes and mortality were seen in most A(H5N1) and A(H7N9) cases despite oseltamivir therapy highlighting the need for improving antiviral strategies against these AIV.