The potential of tumor suppressor genes (TSGs) to serve as clinical markers for disease detection, progression, and therapeutic response was evaluated by conducting a comprehensive review of the English-language scientific literature on aberrant promoter methylation of TSGs in non-small cell lung cancer (NSCLC). Genome-wide hypermethylation and silencing of TSGs are common features of cancer cells. Aberrant promoter methylation has been found in NSCLC, and research is now focused on the identification of specific genes that exhibit differential expression levels based on the methylation state. Aberrant methylation in NSCLC is observed in the early development of cancer and can be detected in DNA circulating in the blood or isolated from sputum. Therefore, methylation assays offer the promise of a noninvasive test for detecting cancer. In addition, the identification of cancer-specific epigenetic changes may be useful for molecular classification and disease stratification. Hence, the detection of cancer-specific methylation changes heralds an exciting new era in the diagnosis of cancer, its prognosis, and therapeutic responsiveness, and warrants further investigation in NSCLC.