Phospholipid hydroperoxide glutathione peroxidase (PHGPx), now known as GPx-4, was discovered in 1982 as a second glutathione peroxidase (GPx) distinct from GPx-1 because it could peculiarly protect membrane lipid peroxidation in the presence of Vitamin E. This cooperation was explained by the hydroperoxyl radical scavenging capacity of vitamin E and the reduction of membrane phosholipid hydroperoxide (PLOOH) by PHGPx. Later, kinetic analysis indicated that in the presence of PCOOH, the oxidizing step of the catalytic cycle is very fast (measured k’+1 values of 107 M-1 s-1 for human and porcine GPx-4) while reduction is the rate-limiting step of the overall reaction. Comparison of k’+2 values suggests that, among the SecGPxs, PHGPx has the lowest reactivity with GSH. Indeed PHGPx reacts five times as fast with dithiothreitol than with GSH and almost equally fast with mercaptoethanol, when none of these thiols is accepted by GPx-1. These early findings anticipated the broadest physiological role of this enzyme compared to the other GPxs that emerged year after year, and today is fully confirmed by k.o models. The vital role of GPx-4 could actually be ascribed to the enzyme antiperoxidant activity and was found definitely relevant for neurons. Intriguing enough, Vitamin E could to rescue the dead phenotype obtained in cells by switching off the expression of the GPx-4. On the other hand, the central role in fertility of GPx-4, allowing ‘moonlighting’ to a structural component of the sperm mitochondrial capsules by oxidizing specific protein thiols, can be ascribed to its broad thiol specificity. In the meanwhile, CysGPx were discovered bearing the structural characteristics of PHGPx and found as efficient as their Sec-containing homologues in reducing hydroperoxides. The majority of these proteins, which indeed reduce efficiently PCOOH, are confined to the invertebrate and plant kingdom. Typically they contain a CR residue within a functional helix and are linked to the thioredoxin but not the GSH system. Some of them emerged for unespected novel roles such as peroxide sensing and gene activation. All together these finding expand our apreciation of lipid peroxidation to a physiologically relevant phenomena, and qualify redox regulation is a complementary mechanism to the other most known post-translational modifications. In the present scenario, understanding the molecular details of these signaling cascades and defining the specific role of each individual GPx in this context is anticipated as extremely rewarding and full of surprises. Further, it appears indeed the ground for developing effective strategies to counteract major human pathological processes such as cancer and cerebral degeneration.