OBJECTIVE A subset of patients being treated for hypothyroidism do not feel well while taking levothyroxine (LT4) replacement therapy, despite having a normal serum thyroid stimulating hormone level. Pursuing a relative triiodothyronine deficiency as a potential explanation for patient dissatisfaction, has led to trials of combination therapy with liothyronine (LT3), with largely negative outcomes. This review attempts to reconcile these diverse findings, consider potential explanations, and identify areas for future research. RESULTS Patients being treated with LT4 often have lower triiodothyronine levels than patients with endogenous thyroid function. Linking patient dissatisfaction with low triiodothyronine levels has fueled multiple combination therapy trials that have generally not shown improvement in patient quality of life, mood, or cognitive performance. Some trials, however, suggest patient preference for combination therapy. There continues, moreover, to be anecdotal evidence that patients have fewer unresolved symptoms while taking combination therapy. CONCLUSIONS The 14 trials completed to date have suffered from employing doses of LT3 that do not result in steady triiodothyronine levels, and having insufficient power to analyze results based on baseline dissatisfaction with therapy and patient genotype. Future trials that are able to incorporate such features may provide insight into what thyroid hormone preparations will most improve patient satisfaction with therapy.