Hydrolytic, oxidative and reductive dehalogenation in mammals are relatively poorly understood processes, yet they are critical biochemical reactions for living systems. In this lecture, data generated by our research group and by others related to the physiological role of the different deiodinating enzymes, with emphasis on the reductive iodotyrosine dehalogenase (IYD) and the type 1, 2 and 3 iodothyronine selenodeiodinases (D1, D2 & D3) will be discussed. Their structural mechanism of action, expression distribution and synthesis, and their pathophysiological significance as currently known will be summarized, leading ultimately, to the final question: “Are these systems possible novel targets for new diagnostic and therapeutic molecules waiting to be explored in a wide variety of diseases?”