This research aims to understand knowledge bases in urban systems of innovation and entrepreneurship. Using principal component analysis, it develops a new typology that differentiates urban knowledge bases into management knowledge, biomedical knowledge, engineering knowledge, arts and humanities knowledge, transportation knowledge and agricultural knowledge. The following multivariate analysis shows that management knowledge and engineering knowledge are of major importance in facilitating innovation and high technology entrepreneurship in US cities. Additionally, arts and humanities knowledge is positively associated with innovation but not with entrepreneurship. This research sheds light on public policy to build a vibrant urban system of innovation and entrepreneurship.