How can we comprehend the complexity of life at the cellular level when pathways and regulatory mechanisms are so inherently intertwined and redundant? This issue is at the core of every biological question and is both a hurdle and an opportunity in our endeavors to understand how cellular pathways function in a coordinated manner. One proposed approach to overcome this problem is to study pathways inso-called “orthogonal” systems through the use of “synthetic biology,” a term coined in 1912 (1), long before the advent of molecular biology. This approach follows engineering principles for the reconstitution of a biological pathway in an organism or system that does not interact with that path-way (2). This is a complex task that requires prior knowledge, precise experimental design, and multidisciplinary research that includes the formulation of mathematical models to infer novel mechanisms. Lavilla-Puerta et al. (3) have reached a new high in the reconstitution of plant low oxygen(hypoxia) sensing and response mechanisms using the baker’s yeast Saccharomyces cerevisiae to explore and identify new components and regulatory mechanisms that underpin hypoxia sensing and response in plants.