AbstractMotivationSimulations of cancer evolution are highly useful to study the effects of selection and mutation rates on cellular fitness. However, most methods are either lattice-based and cannot simulate realistically sized tumours, or they omit spatial constraints and lack the clonal dynamics of real-world tumours.ResultsStochastic model of intra-tumour heterogeneity (SMITH) is an efficient and explainable model of cancer evolution that combines a branching process with a new confinement mechanism limiting clonal growth based on the size of the individual clones as well as the overall tumour population. We demonstrate how confinement is sufficient to induce the rich clonal dynamics observed in spatial models and cancer samples across tumour types, while allowing for a clear geometric interpretation and simulation of 1 billion cells within a few minutes on a desktop PC.Availability and implementationSMITH is implemented in C# and freely available at https://bitbucket.org/schwarzlab/smith. For visualizations, we provide the accompanying Python package PyFish at https://bitbucket.org/schwarzlab/pyfish.Supplementary informationSupplementary data are available at Bioinformatics online.