The overall premise of my research is that a greater understanding of how childhood cancer cells respond to extra- or intracellular signals is necessary to identify tumour-specific pathways. Only then can these pathways be targeted therapeutically in a manner that minimizes effects on normal cells. This is especially important in childhood cancer to avoid toxic effects of treatments on the intellectual, physical, and emotional development of a growing child. An ongoing difficulty with this approach is how to find the relevant pathways to target. Over the years we have chosen to characterize recurrent genetic alterations in childhood tumours as a means to more efficiently identify novel cancer genes. This is part of our belief that analysis of primary tumours is preferable for initial identification of pathophysiologically relevant alterations in human malignancies. With the advent of next-generation sequencing, we are now extending this approach to whole genome sequencing of childhood cancers to better understand the mutational landscape of these tumours. Then, once the involved proteins have been identified, model systems can be invoked to further study their biology and how the pathways they are involved in become activated. We then use various biochemical approaches as well as high-throughput platforms such as RNA interference screening to rigorously characterize the involved proteins, their functional interactors, and the signal transduction pathways they participate in. This forms the basis for subsequent strategies to therapeutically target candidate proteins in childhood cancers.