My scientific career started at an extraordinary time, shortly after the discoveries of the helical structure of DNA, the central dogma of DNA to RNA to protein, and the genetic code. Part I of this series emphasizes my education and early studies highlighted by the isolation and characterization of numerous vaccinia virus enzymes, determination of the cap structure of messenger RNA, and development of poxviruses as gene expression vectors for use as recombinant vaccines. Here I describe a shift in my research focus to combine molecular biology and genetics for a comprehensive understanding of poxvirus biology. The dominant paradigm during the early years was to select a function, isolate the responsible proteins, and locate the corresponding gene, whereas later the common paradigm was to select a gene, make a mutation, and determine the altered function. Motivations, behind-the-scenes insights, importance of new technologies, and the vital roles of trainees and coworkers are emphasized. Expected final online publication date for the , Volume 7 is September 29, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.