Methionine sulfoxide reductase enzymes are a protective system against biological oxidative stress in aerobic organisms. Modifications to this antioxidant system have been shown to impact the lifespan of several model system organisms. In humans, methionine oxidation of critical proteins and deficiencies in the methionine sulfoxide reductase system have been linked to age-related diseases, including cancer and neurodegenerative disease. Substrates for methionine sulfoxide reductases have been reviewed multiple times, and are still an active area of discovery. In contrast, less is known about the genetic regulation of methionine sulfoxide reductases. In this review, we discuss studies on the genetic regulation of the methionine sulfoxide reductase system with relevance to longevity and age-related diseases. A better understanding of genetic regulation for methionine sulfoxide reductases may lead to new therapeutic approaches for age-related diseases in the future.