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This article explores the relationship between knowledge creation, entrepreneurship, and economic growth in the United States over the last 150 years. Distinguishing between general knowledge and economically useful knowledge, we examine the changes over time in the locus and content of new knowledge creation: the role of universities, particularly engineering schools and land-grant universities, industrial laboratories, and corporate research and development (R&D) laboratories prior to World War II. The practical orientation of US academic R&D and the close research interaction between academia and industry are noted. We study the unprecedented increase in R&D spending in the United States during and after World War II and how it was converted into economic activity via incumbent firms in the early postwar period and increasingly via new ventures in the last few decades.