The remarkable stability of the human genome is lost in cancer cells due to the loss of efficient and accurate repair in the context of oncogene-induced replication stress and elevated transcription. DNA replication is furthermore emerging as a surprisingly fragile and complex process requiring fork protection and restart, R-loop resolution, and repair. Unresolved replication and repair intermediates signal apoptosis. The synthetic lethality and essentiality resulting from replication-repair stresses thus suggest repair inhibitors as tools to control pathway selection and damage outcomes and to design advanced therapeutics. The 2018 DNA Replication and Repair Structures & Cancer conference will focus on structural and mechanistic insights into dynamic protein, DNA and RNA complexes acting in DNA replication and repair events relevant to cancer.