It was originally proposed that tumour suppressor genes (TSGs) act in a recessive manner. Instead, numerous TSGs, including p53 and PTEN, exhibit haplo‐insufficiency as a consequence of the dose‐dependency of TSG function. Due to the challenges of identifying haplo‐insufficient TSGs by human genetics analysis alone, mouse models play a pivotal role in firmly establishing the haplo‐insufficiency of a gene, as in the recent identification of DOK2 as a haplo‐insufficient lung TSG. In many cases, TSGs exhibit conditional or compound haplo‐insufficiency, in which loss of one TSG allele is functionally important only in certain settings or after compound loss of other genes. The 5q deletion syndrome (5q⁻) is a paradigm of compound haplo‐insufficiency and demonstrates the importance of combinatorial interactions to elicit specific phenotypes. These concepts must be integrated into basic science studies to avoid delay in the identification of important TSGs. In the clinical realm, the challenges for molecular pathologists are the development of quantitative measures that can accurately and systematically ascertain the status of haplo‐insufficient genes in tumour biopsies, and the use of this information to accurately predict prognosis and response to therapy. Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.