Our group uses a biochemical approach to study signal transduction in leukaemia cells. The overall emphasis is to use insights provided by these studies to identify novel drugs and strategies which can be used to induce more effective apoptotic killing of chronic lymphocytic leukaemia (CLL) cells than is possible using conventional chemotherapy. Recent studies fall into two principle categories, as outlined below. The first approach involves the p53 gene and its protein product which plays a key role in inducing apoptosis following treatment with conventional agents. Mutation of this gene frequently contributes to drug resistance in CLL and in other cancers, therefore drugs which kill cells independently of p53 are of potential value in the treatment of CLL patients who have become resistant to standards regimes. These studies have resulted in the identification of three novel drugs which induce CLL apoptosis regardless of the mutation status of the p53 gene, but which are relatively inactive against normal cells. The second approach attempts to define biochemical signalling strategies used by CLL cells to avoid apoptosis induction following treatment with cytotoxic agents. Some of these strategies are cell-intrinsic and include constitutive activation of STAT3, MAP kinase and PI-3kinase signalling pathways, while others involve signalling to CLL cells from extrinsic cytoprotective cytokines including IL-4. Understanding of these mechanisms has resulted in the identification of highly selective small molecule inhibitors which antagonize the protective mechanisms and result in more efficient cell killing.