The low-triiodothyronine (T3) syndrome, also referred as non thyroidal illness, is a frequent finding usually associated to a wide constellation of both acute and chronic extra-thyroid critical disorders that largely differ each other in terms of aetiology, organ involvement, evolution, and clinical impact. Independently of its origin, severity and time-course, the low-T3 syndrome has been always considered an adaptive and positive process not needing specific treatment. More recently this concept has been challenged due the emerging experimental and clinical evidences of a fundamental role of thyroid hormone as a crucial homeostatic multi-action/multi-organ factor to preserve in particular cardiovascular system and other pathophysiologically-related vital organs such as kidney and brain. The presence and relevance of a tissue hypothyroidism secondary to a low T3 or a low T3/T4 state, at least in some forms of critical diseases, may likely be underestimated. A close association between low T3 and poor prognosis in large populations of cardiac patients has been provided, and some pilot clinical studies have been reported showing a significant improvement in terms of both cardiac function and neuroendocrine balance in both acute and chronic cardiac diseases after administration of replacement doses of synthetic thyroid hormone. Multi-center large trials documenting functional and prognostic benefits of treatment are, however, lacking; also, effective end-points, timing, type and doses of hormone replacement are largely undefined. The impact of thyroid hormone-based therapy namely in post-ischemic and idiopathic heart failure, if hypothesis is proved correct, could dramatically improve both patient health care and public health costs.