When the Human Genome Project released its initial draft sequence in 2001, it marked the culmination of over a decade of work and an estimated $3 billion in research costs. President Bill Clinton hailed it as "the most wondrous map ever produced by mankind," while Prime Minister Tony Blair predicted a medical revolution surpassing even the discovery of antibiotics. The quest to sequence a human genome had begun in 1990, building on decades of protein and RNA sequencing research dating back to the 1940s.

In the twenty years following that initial draft, the average sequencing cost per genome plummeted roughly one hundred thousand-fold, ending up just north of $500. The cost to sequence a million letters or "megabase" of DNA fell to six tenths of a cent. This dramatic price drop resulted from technological innovation including new sequencing chemistries, computational methods for assembling raw reads into finished genomes, and highly efficient commercial sequencing machines. Out of the many sequencing methods developed over the decades, five proved particularly important.

Fred Sanger, biology's great decoder, invented methods that would dominate the field for decades. After winning his first Nobel Prize in 1958 for protein sequencing, Sanger developed the "plus and minus" technique in 1975 and the simpler "chain termination" method in 1977, now known as Sanger sequencing. His fluorescently labeled nucleotides in 1986 paved the way for automated sequencing, transforming a painstaking manual process into the high-throughput technology that would make genome sequencing accessible to researchers worldwide.