Extrachromosomal Circular DNA is emerging as a new frontier for biomedical research. Unlike the typical chromosome, which is linear, circular DNA does not have free ends. This circularity nature makes them defy much of the knowledge we have learned from the textbook, making this an exciting topic to uncover new biologies. Meanwhile, Circular DNA abundantly exists from plants to animals, including humans. Strikingly, now we know circular DNA is present in nearly 30% of cancer patients (known as extrachromosomal circular DNA, ecDNA). Circular DNA appears to be a common mechanism for cancer cells to amplify their oncogenes, driving tumor initiation and progression, and strongly attracting industry interest to target circular DNA biology for cancer therapy.