It is now more than a decade since the first commercially successful genetically engineered agricultural crops were launched (Castle et al., 2006). These first products were based in large part on simple monogenic traits, such as herbicide tolerance or insect resistance, which did not require manipulation of complex molecular pathways in the transgenic plant. Since then, there has been a growing expectation that the biotechnology industry will deliver a second generation of transgenic products for more challenging traits relating to yield and yield stability, which are under complex polygenic control (Gutterson and Zhang, 2004; Salmeron and Herrera-Estrella, 2006). Advances in plant genomics and systems biology, including the availability of the complete genome sequences of both Arabidopsis (Arabidopsis thaliana) and rice (Oryza sativa), have offered an unprecedented opportunity to identify regulatory genes and networks that control these important traits. Because transcription factors (TFs) naturally act as master regulators of cellular processes, they are expected to be excellent candidates for modifying complex traits in crop plants, and TF-based technologies are likely to be a prominent part of the next generation of successful biotechnology crops. In this article, we review the prospects for modification of these target traits by TF regulation, including some of the challenges associated with such a strategy.