Smoking is directly responsible for approximately 90% of lung cancers and is also strongly associated with cancers of the head and neck, esophagus and urinary bladder. Our growing understanding of the molecular changes that underlie cancer progression has contributed to the development of novel molecular approaches for the detection of cancer. In this study, we review a number of recent studies that have used molecular techniques to detect neoplastic DNA from lung, head and neck, esophagus and bladder cancer. The majority of these approaches are based on polymerase chain reaction (PCR) based assays. These PCR-based techniques can detect a few clonal cancer cells containing a specific DNA mutation, microsatellite alteration, or CpG island methylation among an excess background of normal cells. The ability to accurately detect a small number of malignant cells in a wide range of clinical specimens including sputum, saliva, bronchoalveolar lavage fluid, urine, serum, plasma, or tissue has significant implications for screening high-risk individuals (such as cigarette smokers) for cancer.