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Transcriptional profiling of entire tumors has yielded considerable insight into the molecular mechanisms of heterogeneous cell populations within different types of neoplasms. The data thus acquired can be further refined by microdissection methods that enable the analyses of subpopulations of neoplastic cells. Separation of the various components of a neoplasm (i.e., stromal cells, inflammatory infiltrates, and blood vessels) has been problematic, primarily because of a paucity of tools for accurate microdissection. The advent of laser capture microdissection combined with powerful tools of linear amplification of RNA and high-throughput microarray-based assays have allowed the transcriptional mapping of intricate and highly complex networks within pure populations of neoplastic cells. With this approach, specific "molecular signatures" can be assigned to tumors of distinct or even similar histomorphology, thereby aiding the desired objective of pattern recognition, tumor classification, and prognostication. This review highlights the potential benefits of global gene expression profiling of tumor cells as a complement to conventional histopathologic analyses.