Bone metastases are common in patients with non–small cell lung cancer (NSCLC), often causing pain and a decrease in quality of life (QoL). The effect of bone-targeted agents is evaluated by reduction in skeletal-related events in which neither pain nor QoL are included. Radioisotopes can be administered for more diffuse bone pain that is not eligible for palliative radiotherapy. The evidence that bone-targeted agents relieve pain or improve QoL is not solid. We performed a systematic review of the effect of bone-targeted agents on pain and QoL in patients with NSCLC. Our systematic literature search included original articles or abstracts reporting on bisphosphonates, denosumab, or radioisotopes or combinations thereof in patients with bone metastases (≥5 patients with NSCLC), with pain, QoL, or both serving as the primary or secondary end point. Of the twenty-five eligible studies, 13 examined bisphosphonates (one also examined denosumab) and 12 dealt with radioisotopes. None of the randomized studies on bisphosphonates or denosumab evaluated pain and QoL as the primary end point. In the single-arm studies of bisphosphonates a decrease in pain or analgesic consumption was found for 38% to 77% of patients. QoL was included in five of 13 studies, but improvement was found in only two. No high-level evidence that bisphosphonates or denosumab reduce pain or improve QoL was found. Although the data are limited, radioisotopes seem to reduce pain with a rapid onset of action and duration of response of 1 to 3 months. The evidence that bisphosphonates or denosumab reduce or prevent pain in patients with NSCLC and bone metastases or that they have an influence on QoL is very weak. Radioisotopes can be used to reduce diffuse pain, although there is no high-level evidence supporting such use.