We are pleased to introduce this Special Issue of Environmental and Molecular Mutagenesis, which contains a collection of papers written on the occasion of the 50th anniversary of the founding in 1969 of the Environmental Mutagenesis and Genomics Society (EMGS), formerly the Environmental Mutagen Society (EMS). This issue opens with a historical review by David DeMarini of the scientific and social events prior to 1969 and how those events converged to cause a group of concerned scientists to form the EMGS. This is followed by a brief summary of the current status of the Society and future directions by Miriam Poirier, the Society's outgoing president. Philip Hanawalt and Joann Sweasy provide a commentary touching on our Society's history in understanding the mechanisms underlying cellular responses to genomic stress. This commentary highlights ground-breaking scientific advances in the field of DNA repair, future directions for this field of research, and the critical intersection of basic and applied research. They also note the important role that EMGS plays as the ideal professional society for researchers in the field of DNA repair and for the need to expand the global outreach of the Society beyond the activities sponsored by the Hollaender Committee of the EMGS. One of the original goals of the EMGS was to support the research efforts and develop the tools necessary to identify potential human germ-cell mutagens. Although much has been done in this regard, no agent has yet been identified definitively as a human germ-cell mutagen. Thus, Francesco Marchetti and colleagues review this important area of research and note the need for further work, in particular, in the application of state-of-the-art genomic tools, to identify such agents. The value of quantitative mutagenesis assessments, derived from dose–response data, is noted by Robert Heflich and colleagues who urge the use of such data to improve the toxicological assessment of health risks from mutagenic agents. Paul White, Alexandra Long, and George Johnson describe considerations in transitioning from the use of genotoxicity endpoints exclusively for hazard identification toward their inclusion in quantitative risk assessment. The latest advances and new analyses in this area are presented along with a discussion of work required to develop standards for interpretation of quantitative mutagenicity data in this regulatory paradigm change. These concepts are applied in a case study by Mirjam Luijten and colleagues in their quantitative evaluation of benzene through application of the “Clean Sheet” approach to risk assessment. In addition, Joanna Klapacz and Bhaskar Gollapudi show how dose–response mutation analysis, along with other tools, can benefit regulatory decisions on human risk. Aligned with the concept of mutagenicity (permanent genomic damage) as a regulatory endpoint, Jennifer Sasaki and colleagues provide examples of adverse outcome pathways (AOPs) that culminate in mutations, chromosomal aberrations, and aneuploidy. These authors describe the utility of the AOP framework for developing testing strategies to identify modes of action using mechanistic assays and describe a case example of application. Kelly Harris and colleagues describe an approach to developing panels of hotspot cancer driver gene mutations that could be used as biomarkers of cancer risk. This innovative effort could be joined with efforts in precision medicine to improve the treatment and cure of cancer. In addition to mutation, altered gene expression is also critical to the development of cancer and of germ-line transmission of health effects. Roger Godschalk and colleagues argue that early life exposures may lead to enhanced mutagenicity through mutation fixation in rapidly dividing tissues and subsequent clonal expansion during normal development. This overlooked area in genetic toxicology warrants further attention because these mosaic mutations are likely to impact tissue function and may be causative factors in cancer and other genetic diseases. Jesse Salk and Scott Kennedy review novel error-corrected next-generation sequencing technologies, such as Duplex Sequencing, that can be used to identify de novo and clonally expanded mutations. These transformative sequencing technologies reduce technical errors to low enough rates to be used in quantifying somatic cell mutation frequencies, and enable mutation analysis in any organism, cell/tissue, or gene (including cancer driver mutations). These tools are poised to revolutionize genetic toxicology testing. The final review article in the Special Issue focuses on one of the newest areas of interest in the EMGS: epigenomics. Bambarendage Perera and colleagues review the rapidly emerging developments in the field of environmental epigenomics and how environmental exposures can alter the regulatory networks that govern gene expression. The Special Issue concludes with examples of basic and applied genetic toxicology studies. Takehiko Nohmi and Kyomu Matsumoto describe the effect of DNA polymerase kappa and mismatch repair on dose–responses of chromosome aberrations induced by oxidative agents. Deborah Roubicek and colleagues summarize their 20-year monitoring of the mutagenicity of surface waters used to make drinking water in the State of São Paulo, Brazil. Both papers illustrate the importance of both basic and applied environmental mutagenesis research. Collectively, these papers highlight the past accomplishments of the EMGS and the exciting future that it will support and nurture.