Subclinical Hypothyroidism (SCH) is defined as a raised level of serum TSH level in the presence of normal circulating free thyroid hormones. SCH is a highly prevalent condition displaying some peculiarities, both in terms of the diagnostic and therapeutic approach, when specific population and/or concomitant diseases are taken into account. The debate upon whether LT4 therapy should be initiated or not in patients with SCH is a long lasting one and still it remains controversial. Current evidence supports the concept that the clinical consequences of SCH may be profoundly different in relation to several patient-specific characteristics. Aim of the present review is to provide updated indications for SCH treatment in specific clinical settings. These will include the management of SCH in obese and diabetic patients, in pregnant women, and in specific age groups. Treatment modalities, including LT4 doses and recommended follow-up strategy will also be discussed. In the era of "precision medicine" the decision to-treat-not-to-treat SCH should be individualized taking into account risks and beneficial outcomes of LT4 therapy. With this in mind, we reviewed the most relevant studies in the recent literature in order to provide evidence for or against LT4 replacement therapy for SCH in specific clinical settings.