The article evaluates the state of high-tech and knowledge-intensive business in the regions of the Siberian Federal District and identifies their development constraints and prospects. Approaches to defining high-tech business are compared. Estimates are given for the spatial and sectoral structure of high-tech and knowledge-intensive business. An outline is given of the challenges and opportunities for the development of high-tech manufacturers and service-providers. It is shown that the role of high-tech and knowledge-intensive business in Siberia remains low: they form less than 10% of the regional economy. The service economy, represented by high-tech services, is developing at a higher pace in Siberia: air transportation services come first, followed by high-tech industrial services and small high-tech processing companies. Large high-tech companies are dependent on the government strategy. A strong differentiation exists between the regions of the Siberian Federal District in terms of presence and development of high-tech business. Novosibirsk oblast, Krasnoyarsk krai, and Irkutsk oblast can be considered regional leaders in high-tech production. Empirical data confirms that the most favorable conditions for the development of the new economy exist in regions with advanced science and education.