This article marks the 20th anniversary of the sequencing of the first genome from a living species and the 15th anniversary of the White House announcement of the first draft of the human genome sequence. The authors, J. Craig Venter, Hamilton O. Smith, and Mark D. Adams, reflect on the significance of their work in 2001, which used a whole-genome shotgun (WGS) strategy to sequence the human genome. This method was considered radical at the time but proved to be faster, cheaper, and more effective than the clone-by-clone approach used by the federal Human Genome Project. The article highlights the challenges and achievements in understanding the human genome, including the discovery of the actual number of protein-coding genes (around 20,000) and the importance of non-coding RNAs in gene regulation. It also discusses the unique genetic variations among individuals and the implications for disease risk and trait determination. The success of the WGS method has led to its widespread adoption, with modern sequencing technologies now capable of sequencing thousands of genomes per month at a much lower cost.This article marks the 20th anniversary of the sequencing of the first genome from a living species and the 15th anniversary of the White House announcement of the first draft of the human genome sequence. The authors, J. Craig Venter, Hamilton O. Smith, and Mark D. Adams, reflect on the significance of their work in 2001, which used a whole-genome shotgun (WGS) strategy to sequence the human genome. This method was considered radical at the time but proved to be faster, cheaper, and more effective than the clone-by-clone approach used by the federal Human Genome Project. The article highlights the challenges and achievements in understanding the human genome, including the discovery of the actual number of protein-coding genes (around 20,000) and the importance of non-coding RNAs in gene regulation. It also discusses the unique genetic variations among individuals and the implications for disease risk and trait determination. The success of the WGS method has led to its widespread adoption, with modern sequencing technologies now capable of sequencing thousands of genomes per month at a much lower cost.