Since the first introduction of sodium iodide I-131 for use with thyroid patients almost 80 years ago, more than 50 radiopharmaceuticals have reached the markets for a wide range of diseases, especially cancers. The nuclear medicine paradigm also shifts from solely molecular imaging or radionuclide therapy to imaging-guided radionuclide therapy, which is deemed a vital component of precision cancer therapy and an emerging medical modality for personalized medicine. The imaging-guided radionuclide therapy highlights the systematic integration of targeted nuclear diagnostics and radionuclide therapeutics. Regarding this, nuclear imaging serves to “visualize” the lesions and guide the therapeutic strategy, followed by administration of a precise patient specific dose of radiotherapeutics for treatment according to the absorbed dose to different organs and tumors calculated by dosimetry tools, and finally repeated imaging to predict the prognosis. This strategy leads to significantly enhanced therapeutic efficacy, improved patient outcomes, and manageable adverse events. In this review, we provide an overview of imaging-guided targeted radionuclide therapy for different tumors such as advanced prostate cancer and neuroendocrine tumors, with a focus on development of new radioligands and their preclinical and clinical results, and further discuss about challenges and future perspectives.