Red blood cells (RBCs) have been historically regarded as a critical model to investigate cellular and oxidant stress biology. First of all, they are constantly exposed to oxidant stress, as their main function is to transport and deliver oxygen to tissues. Second, they are devoid of de novo protein synthesis capacity, which prevents RBCs from replacing irreversibly oxidised proteins with newly synthesised ones. As such, RBCs have evolved to (i) protect themselves from oxidant stress, in order to prevent oxidant damage from reactive species; (ii) repair oxidatively damaged proteins, through mechanisms that involve glutathione and one-carbon metabolism; (iii) destroy irreversibly oxidised proteins through proteasomal or protease-dependent degradation; and (iv) sacrifice membrane portions through mechanism of vesiculation. In this brief review we will summarize these processes and their relevance to RBC redox biology (within the context of blood storage), with a focus on how polymorphisms in RBC antioxidant responses could contribute to explaining the heterogeneity in the progression and severity of the RBC storage lesion that can be observed across the healthy donor population.