We use molecular genetics to understand the mechanisms underlying developmental determination during mammalian embryogenesis. Variation in the activity and abundance of transcription factors is generally acknowledged to be a regulatory focal point where signal cascades converge and are transduced into specific cellular responses. Regulation of the basal transcriptional apparatus is instructed through DNA:protein interactions mediated by specific transcription factors and accessory proteins. The underlying question we address is: how are tissues and organs generated, and how are they instructed to fulfill their differentiated fates? This most basic question can be dissected into components by addressing the multiple activities of individual transcription factor proteins and their genes. How do tissue-restricted transcription factors mediate such an enormous variety of potential responses, and how do aberrant responses lead to human cancer and other diseases? Our approach to these problems all employ mouse germ line gene manipulation. These studies have led to surprising insights into the developmental origin and elaboration of differentiated function in the central and peripheral nervous system, the kidney, the cardiovascular system and blood. We also continue to explore the molecular basis of globin gene regulation, as it comprises one of the most advanced models for chromatin-modulated gene regulatory complexity.