Modelling the genesis of human cancers is at a scientific turning point. Starting from primary sources of normal human cells, it is now possible to reproducibly generate several types of malignant cell populations. Powerful methods for clonally tracking and manipulating their appearance and progression in serially transplanted immunodeficient mice are also in place. These developments circumvent historic drawbacks inherent in analyses of cancers produced in model organisms, established human malignant cell lines, or highly heterogeneous patient samples. In this review, we survey the advantages, contributions and limitations of current de novo human tumorigenesis strategies and note several exciting prospects on the horizon.