Both solid tumours and leukaemias show considerable histological and functional heterogeneity. It is widely accepted that genetic lesions have a major role in determining tumour phenotype, but evidence is also accumulating that cancers of distinct subtypes within an organ may derive from different 'cells of origin'. These cells acquire the first genetic hit or hits that culminate in the initiation of cancer. The identification of these crucial target cell populations may allow earlier detection of malignancies and better prediction of tumour behaviour, and ultimately may lead to preventive therapies for individuals at high risk of developing cancer.