The 2014 Gordon Research Conference on Mutagenesis will focus on the causes and consequences of changes to the genetic landscape. The genome of all organisms is constantly faced with genetic changes, some of which drive human diseases such as cancer, neurological disorders and premature aging. Recent findings have revealed important new understanding of how mutagenesis stems from the success—or failure—of key cellular factors in DNA transactions. The conference will highlight new work encompassing a broad range of approaches, from mechanistic studies of mutagenesis to the recent revolution in whole-genome analysis. Provisional session titles include RNA-mediated mutagenesis; Genomic and chromosomal alterations; Challenges at the replication fork; Editing and repair; Decision points, repair or mutate; DNA polymerases and translesion synthesis; DNA structural challenges; and Targeted mutagenesis. The sessions will be based on presentations by leading scientists, interspersed with short talks, by younger investigators, selected from submitted abstracts. The schedule includes vibrant group discussions, poster sessions and ample time for individual interactions. The key goals of the conference are to bring together people representing diverse approaches in mutagenesis, to stimulate presentation and discussion of new ideas, to catalyze new collaborations and to encourage full involvement by those new to the field. The spectacular setting in Girona, Spain is an added benefit that will help ensure a productive and enjoyable conference.