In the early 1970s, Sulfolobus was first isolated by Thomas Brock and co-workers from sulfur-rich acidic hot springs in Yellowstone National Park. Sulfolobus became one of the model organisms of Archaea in general, and of Crenarchaea in particular. Many of its unusual physiological characteristics have been investigated, and several of its thermostable enzymes have been studied in considerable detail. For fundamental reasons, and because of its potential for industrial applications, Sulfolobus has been selected for a genome sequence project. The recent completion of the Sulfolobus solfataricus genome has set the stage for a series of postgenome research lines that will be reviewed here. Comparative genomics aims to unravel the cell’s metabolic potential (enzymes, pathways, and regulation) and compare it to other organisms. This in silico analysis of Sulfolobus has revealed several unique metabolic features and confirmed that the major control processes (transcription, translation, and replication) resemble eukaryal much more than bacterial equivalents. Currently, several research groups use a functional genomics approach—a genomebased, high-throughput analysis of the complete Sulfolobus cell—at the level of RNA (transcriptomics), protein (proteomics), and metabolic intermediates and products (metabolomics). Apart from analyzing the cell’s response to different cultivation conditions, the comparison of different genotypes (wild type and mutants) would be very interesting for both basic science and applied reasons. Much effort has recently been put into the establishment of tools that allow genetic engineering of Sulfolobus. The future challenge is to integrate available knowledge in order to understand the relevant mechanisms that enable Sulfolobus to thrive in its extreme habitats. Moreover, such a Systems Biology approach is essential as a basis for the directed engineering and industrial exploitation of this unique microorganism.