It is debatable whether treatment of thyroid nodules with thyroid hormones is effective, results of clinical trials, even randomized, being inconclusive, none of them showing significant efficacy of this therapy. Two questions remain unanswered: what is the natural history of these nodules and is it possible to identify patients with these heterogeneous lesions who will respond to treatment? Currently available study data show a marked level of spontaneous regression or even total disappearance of the nodules. Further long-term clinical trials appear indicated, including a sufficient number of patients and a large cohort of untreated patients.