Research in the last few years has focused on the emergence and selection of genetic variants affecting protein functions. However, coding genes represent 2% of the human genome, tumor cells exhibit a wide variety of non-genetic (or epigenetic) alterations, and aberrant transcriptional programs ultimately determine cancer cell phenotypes. The role of the non-coding genome and epigenetic and transcriptional heterogeneity are only now emerging as alternative fuel for tumour evolution, sustained by technological advances to explore tumour heterogeneity at single cell and spatial resolution. This EMBO Workshop will bring together an interdisciplinary community of scientists with the goal of facilitating discussion and collaborations around genetic and non-genetic mechanisms of cancer evolution. The primary objective is to expand the current genetic-centric view with a mechanistic perspective centred around transcriptional and epigenetic alterations.