It is well recognized that some hypothyroid patients on levothyroxine (LT4) remain symptomatic, but why patients are susceptible to this condition, why symptoms persist and what is the role of combination therapy with LT4 and liothyronine (LT3), are questions that remain unclear. Here we explore evidence of abnormal thyroid hormone (TH) metabolism in LT4-treated patients, and offer a rationale for why some patients perceive LT4 therapy as a failure.The review is based on a collection of primary and review literature gathered from a PubMed search of hypothyroidism, levothyroxine, liothyronine, and desiccated thyroid extract, among other keywords. PubMed searches were supplemented by Google Scholar and the authors' prior knowledge of the subject.In most LT4-treated patients, normalization of serum TSH levels results in decreased serum T3/T4 ratio, with relatively lower serum T3 levels; in at least 15% of the cases, serum T3 levels are below normal. These changes can lead to a reduction in TH action, which would explain the slower rate of metabolism and elevated serum cholesterol levels. A small percentage of patients might also experience persistent symptoms of hypothyroidism, with impaired cognition and tiredness. We propose that such patients carry a key clinical factor, e.g. specific genetic and/or immunologic makeup, that is well compensated while the thyroid function is normal but might become apparent when compounded with relatively lower serum T3 levels.After excluding other explanations, physicians should openly discuss and consider therapy with LT4 and LT3 with those hypothyroid patients that have persistent symptoms or metabolic abnormalities despite normalization of serum TSH level. New clinical trials focused on symptomatic patients, genetic makeup and comorbidities, with the statistical power to identify differences between monotherapy and combination therapy, are needed.