Despite the recent advances in lung cancer biology, molecular pathology, and treatment, this malignancy remains the leading cause of cancer-related death worldwide and non-small cell lung cancer (NSCLC) is the most common form found at diagnosis. Accurate staging of the disease is a fundamental prognostic factor that correctly predicts progression-free (PFS) and overall survival (OS) of NSCLC patients. However, outcome of patients within each TNM staging group can change widely highlighting the need to identify additional prognostic biomarkers to better stratify patients on the basis of risk. 18F-FDG PET/CT plays an essential role in staging, evaluation of treatment response, and tumoral target delineation in NSCLC patients. Moreover, a number of studies showed the prognostic role of imaging parameters derived from PET images, such as metabolic tumor volume (MTV) and total lesion glycolysis (TLG). These parameters represent three-dimensional PET-based measurements providing information on both tumor volume and metabolic activity and previous studies reported their ability to predict OS and PFS of NSCLC patients. This review will primarily focus on the studies that showed the prognostic and predictive role of MTV and TLG in NSCLC patients, addressing also their potential utility in the new era of immunotherapy of NSCLC.