Thioredoxins are ubiquitous antioxidant enzymes that play important roles in many health-related cellular processes. As such, the fundamental knowledge of how these enzymes work is of prime importance for understanding cellular redox mechanisms and for laying the ground for the development of future therapeutic approaches. Over the past 40 years, a really impressive amount of data has been published on thioredoxins. Here, we review the most significant results that have contributed to our knowledge regarding the structure, the function, and the mechanism of these crucial enzymes.