The 2014 Gordon Research Conference on "DNA damage, mutation and cancer" marks the 50th anniversary of the discovery of excision repair. We will focus upon the manner in which DNA alterations are recognized and processed by cellular enzymes to modulate their mutagenic effects. Multiple proteins may recognize a DNA lesion and impact the pathway choice for its resolution. Furthermore, each step in a repair pathway generates another lesion, often accessible to enzymes from other pathways. Crosstalk between competing and collaborating DNA repair pathways will be an important emphasis in this Conference. We will also explore chemotherapeutic interventions that take advantage of genotypic differences between normal cells and those in a designated tumor. The strategy of synthetic lethality is important in addition to other approaches to selectively inactivate tumor cells. Finally, we will address the role of DNA damage and telomere processing in aging and cancer. Session titles include: Mutations cause cancer, reveal etiology and provide clues for therapy; Sensing environmental genomic damage, finding needles in the haystack; Weak links in the genome, intrinsic challenges to replication and transcription; Cutting edges at the initiation of DNA repair; Oxidative DNA damage and base excision repair, roles of PARP; Mismatch repair and responses to arrested replication; Cell cycle checkpoints and strand-break repair; Designing chemotherapies based upon cancer genotypes; and Relationships of DNA damage to telomere maintenance and aging. The invited speakers, from diverse fields, are encouraged to share their unpublished results, and a number of early career investigators, selected from submitted abstracts, will have the opportunity to present short talks on their exciting research. Poster sessions and open afternoons will provide ample opportunities for engagement between investigators at all levels. We anticipate that scientific interactions during this conference will impact cancer research in significant ways and result in establishing productive multi-disciplinary research collaborations.