The ability to incorporate knowledge and to innovate is conditioning the way firms and territories are engaging in the globalized world. It is therefore not surprising that this should become the focal point for a range of epistemological currents and scientific disciplines that see this as the basis of a new model of socio-economic development. At the same time, a new territorial culture has emerged that focuses on medium-size cities as the key to inducing multiplicative effects on their surrounding areas and halting the concentration effects of large cities. The objective of this article is to carry out a three-pronged comparative analysis of some medium-size towns and cities in Andalusia (Spain): the degree to which they engage in the knowledge society; their ability for innovation and the local collaboration networks that could favor this, and local public development strategies.