The gradual rewiring of transcriptional circuits over evolutionary timescales is a major source of the diversity of life on the planet. Studies in animals have shown how seemingly small changes in gene regulation can have large effects on morphology and physiology and how selective pressures can act on these changes. The underlying principle in these studies is that gene regulation is modular—changes can be made to the expression of a gene at one place and time, without affecting the expression of that gene at other places and times. Genome-wide studies in single cell yeasts, including those described here, have uncovered evidence of massive transcriptional rewiring, indicating that even closely related species regulate their genes using surprisingly different circuitries. The work described in this thesis begins to suggest some general principles guiding the evolution of transcription circuits. Mechanisms by which large sets of co-expressed genes can be rewired (without disrupting co-expression) are proposed and combinatorial regulation is implicated as a catalyst for change in transcriptional networks.