Eliminating errors in next-generation DNA sequencing has proved challenging. Please join Professor Yanyi Huang as he discusses his team’s newly developed error-correction code (ECC) sequencing, a method to greatly improve sequencing accuracy. Combining fluorogenic sequencing-by-synthesis (SBS) with an information theory–based error-correction algorithm, ECC embeds redundancy in sequencing reads by creating three orthogonal degenerate sequences, generated by alternate dual-base reactions. This is similar to encoding and decoding strategies that have proved effective in detecting and correcting errors in information communication and storage. Professor Huang’s work has shown that, when combined with a fluorogenic SBS chemistry with raw accuracy of 98.1%, ECC sequencing provides single-end, error-free sequences up to 200 bp. ECC approaches should enable accurate identification of extremely rare genomic variations in various applications in biology and medicine.