Barrett's esophagus (BE) is the most important and recognizable precursor lesion for esophageal adenocarcinoma (EAC), which is the one of the fastest-growing cancers in the Western world (600 % in the U.S. in the last 40 years), and therefore it is critical to manage the risk of cancer present in BE. New developments in imaging and molecular markers, as well as an armamentarium of novel and effective endoscopic eradication therapy - especially radio-frequency ablation (RFA) and endoscopic mucosal resection (EMR) - are now available to the interventional endoscopist to help curb the significant rise of esophageal adenocarcinoma (EAC). Endoscopic surveillance is currently recommended by most gastroenterology societies worldwide, although there is no data to support this practice in relation to reducing mortality from EAC. Paradoxically, the cancer risk in Barrett's esophagus is being progressively downgraded, which raises fundamental questions about our understanding of the risk factors and molecular biology of the Barrett's metaplasia-dysplasia-adenocarcinoma sequence. The recent discovery of a strong association of transcriptionally active high-risk human papillomavirus (hr-HPV) with Barrett's dysplasia (BD) and EAC may shed some light on this anomaly. It is imperative that we identify the high-risk group of progressors to EAC. While p53 immunohistochemistry is currently probably the best clinical molecular marker for predicting disease progression in BD, we must think outside the box and cast the net wide in search of additional biomarkers (e.g., high-risk human papilloma virus (hr-HPV)].