The advent of high throughput gene expression profiling, from microarrays to sequence based assays has yielded vast insight into the biology of tumors. New technologies are constantly being unveiled which promise to generate more accurate maps of tumor gene deregulation, and demand the development of new strategies in data analysis. This review details the challenges faced in profiling tumor transcriptomes, and highlights the emerging strategies to utilize global profiling approaches to advance our understanding of causal genetic and epigenetic events and their impact on gene expression and tumor phenotype and behavior, through high throughput profiling, and integration of multiple dimensions of genomic data.