It is becoming increasingly clear that the proliferation of human tumours is driven by a small proportion of cells, termed tumour stem cells, which have the properties of self-renewal. On analogy with stem cells for normal tissues, there are likely to be multiple mechanisms, involving both intrinsic cellular properties and microenvironmental factors, which enable tumour stem cells to resist potentially genotoxic agents. Intrinsic properties include maintenance of cells in a predominantly non-cycling state, expression of transport proteins such as P-glycoprotein, protection from induced apoptosis or other forms of cell death, and limitation of diffusion of potential cytotoxins from the bloodstream. In addition, tumour stem cells are likely to contain multiple genetic changes that will potentially activate host immune mechanisms, which are designed to respond to such changes, and the methods by which tumours suppress such mechanisms are of great relevance to drug resistance. A number of methods of overcoming intrinsic multidrug resistance of tumours have been developed but methods for overcoming tumour resistance mediated by host cells are still at an early stage and require further research.