Mammalian cells employ elaborate antioxidant systems to effectively handle reactive oxygen and nitrogen species (ROS and RNS). At the heart of these systems operate two selenoprotein families consisting of glutathione peroxidase (GPx) and thioredoxin reductase (TrxR) enzymes. Although mostly studied in the context of oxidative stress, considerable evidence has amassed to indicate that these selenoenzymes also play important roles in nitrosative stress responses. GPx and TrxR, together with their redox partners, metabolize nitrosothiols and peroxynitrite, two major RNS. As such, these enzymes play active roles in the cellular defense against nitrosative stress. However, under certain conditions, these enzymes are inactivated by nitrosothiols or peroxynitrite, which may exacerbate oxidative and nitrosative stress in cells. The selenol groups in the active sites of GPx and TrxR enzymes are critically involved in these beneficial and detrimental processes. Further elucidation of the biochemical interactions between distinct RNS and GPx/TrxR will lead to a better understanding of the roles of these selenoenzymes in cellular homeostasis and disease.