During the last decade significant progress in molecular genetics and cell biology was made and numerous signal transduction pathways regulating cell growth, differentiation and survival were identified. It is now fairly well understood how accumulation of multiple genetic aberrations lead to deregulation of these signal transduction pathways and cause malignant transformation and tumour progression. Therefore, in many cases specific tumour phenotypes can be linked to specific genetic changes. As a result molecular diagnostics has become an important tool for tumour diagnositics that helps to discriminate specific entities. Further, determination of critical mutations leading to activation of important growth and survival signals can identify targets for specific tumour therapies. Gastrointestinal stromal tumours (GISTs) provide an excellent example of how activating mutations in receptor tyrosine kinases can be used as a tool to predict tumour biology and response to therapy by receptor inhibitors. During therapy secondary receptor mutations may cause resistance to therapy and thus may require additional combinatorial therapies. Therefore, predictive pathology and monitoring response to novel targeted therapies provide new challenges for pathologists and require a broad spectrum of techniques in molecular pathology.