The 2014 joint meeting of the International Society for Cellular Oncology (ISCO) and the European Workshop on Cytogenetics and Molecular Genetics of Solid Tumors (EWCMST), organized by Nick Gilbert, Juan Cigudosa and Bauke Ylstra, was held from 11 to 14 May in Malaga, Spain. Since the previous meeting in 2012, the ever increasing availability of new sequencing technologies has enabled the analysis of cancer genomes at an increasingly greater detail. In addition to structural changes in the genome (i.e., translocations, deletions, amplifications), frequent mutations in important regulatory genes have been found to occur, as also frequent alterations in a large number of epigenetic factors. The challenge now is to relate structural changes in cancer genomes to the underlying disease mechanisms and to reveal opportunities for the design of novel (targeted) therapies. During the meeting, various topics related to these challenges and opportunities were addressed, including those dealing with functional genomics, genome instability, biomarkers and diagnostics, cancer genetics and epigenomics. Special attention was paid to therapy-driven cancer evolution (keynote lecture) and relationships between DNA repair, cancer and ageing (Prof. Ploem lecture). Based on the information presented at the meeting, several aspects of the cancer genome and its functional implications are provided in this report.