Secondary metabolite (SM) production provides biotic and abiotic stress resistance and enables plants to adapt to the environment. Biosynthesis of these metabolites involves a complex interplay between transcription factors (TFs) and regulatory elements, with emerging evidence suggesting an integral role for chromatin dynamics. Here we review key TFs and epigenetic regulators that govern SM biosynthesis in different contexts. We summarize relevant emerging technologies and results from the model species arabidopsis (Arabidopsis thaliana) and outline aspects of regulation that may also function in food, feed, fiber, oil, or industrial crop plants. Finally, we highlight how effective translation of fundamental knowledge from model to non-model species can benefit understanding of SM production in a variety of ecological, agricultural, and pharmaceutical contexts.