The term theranostics is the combination of a diagnostic tool that helps to define the right therapeutic tool for specific disease. It signifies the "we know which sites require treatment (diagnostic scan) and confirm that those sites have been treated (post-therapy scan)" demonstrating the achievable tumor dose concept. This term was first used by John Funkhouser at the beginning of the 90s, at the same time the concept of personalized medicine appeared. In nuclear medicine, theranostics is easy to apply and understand because of an easy switch from diagnosis to therapy with the same vector. It helps in maximizing tumor dose and sparing normal tissue with high specific and rapid uptake in metastasis. The oldest application of this concept is radioactive iodine I-131 (RAI). The first treatment based on the theranostic concept was performed on thyroid cancer patients with RAI in 1946. From then on management of differentiated thyroid cancer (DTC) has evolved on the multimodality concept. We now use the term "our" patient instead of "my" patient to signify this. However, the initial surgical management followed by RAI as per the theranostics has remained the mainstay in achieving a cure in most of DTC patients. The normal thyroid cells metabolise iodine, the principle of which is utilized in imaging of the thyroid gland with isotopes of iodine. RAI treatment of DTC is based on the principle of sodium iodide symporter (NIS) expressing thyroid cells with DTC cells having the ability of trapping circulating RAI successfully helping in treatment of residual and metastatic disease. NIS is usually negative in poorly differentiated cells and is inversely proportional to Glucose transporter receptor Type 1 expression. Both positive and negative NIS are the key components of the theranostic approach in treatment of DTC. Presence or absence of NIS is documented by either whole body iodine scintigraphy (WBS) or 2-deoxy-2(18F) fludeoxyglucose (FDG) positron emission tomography computed tomography (PET-CT). Currently, single photon emission CT and CT (SPECT-CT) has significantly improved the precision and sensitivity of whole body iodine scintigraphy with its capability of accurate localization of disease foci whether iodine avid or non-avid. This has helped in a more personalized approach in treatment. This review will give an overview of the role of NIS in the theranostic approach to management with RAI, its current status and also the molecular approach to treatment in RAI refractory disease.