Multiple primary cancers (MPC) occurring in the same individual is considered rare but being increasingly recognized owing to the longer cancer survival nowadays. Despite of accumulating experience in diagnosis, effective treatment remains to be problematic in many scenarios. Genetic testing-based targeted therapy could be an invaluable option for both diagnosis and treatment of such patients. Here we present a 74-year-old male with triple primary cancers including kidney, prostate, and lung with metastatic tumor on the costal bones. The patient visited the hospital for persistent cough and hemoptysis, and a diagnosis of squamous cell carcinoma of the left lung was made by bioptic fiberoptic bronchoscopy. A previous history included renal cancer controlled by Sorafenib and prostate cancer controlled by Goserelin. Radiotherapy and platinum-based chemotherapy failed to help the patient and the tumor size increased over a period of 6 months. In order to seek better therapeutical options, we performed targeted sequencing using the cancerous tissues from his lung, kidney, and prostate cancers. Briefly, the results identified VHL, EGFR, PIK3CA, TP53, and AKT1 mutations in lung cancer, AKT1, FGFR2, and TP53 mutations in renal cancer, and FGFR2 mutations in prostate cancer. A combined medication targeting PIK3CA and AKT1 signaling was recommended and the patient was given BKM120 (PIK3CA, Phase III clinical trial) and MK2206 (AKT, phase III clinical trial). Revisit chest CTs after 4 months and 9 months showed a significant shrinkage of tumor size by 40% and 80%, respectively. Our experience demonstrated a good example that genetic analysis could be valuable to diagnose and precisely treat multiple primary cancers.