Emerging evidence from the large numbers of cancer genomes analyzed in recent years indicates that chromosomal instability (CI), a well-established hallmark of cancer cells is detectable in precancerous lesions. In this opinion article, we discuss the association of this instability with tumor progression and cancer risk. We highlight the opportunity that early genomic instability presents for the diagnosis of esophageal adenocarcinoma and its precancerous lesion, Barrett’s esophagus. With a growing body of evidence suggesting that only a small pool of cancer-related genes may be involved in early tumor development, we argue that general genomic instability may hold greater diagnostic potential for early cancer detection as opposed to the identification of individual mutational biomarkers.