We explore how the extracellular milieu impacts intracellular decision-making by experimentally controlling the cellular microenvironment or leveraging naturally occurring sources of variation within a tissue. Here, we employ solutions that include controlled culture conditions with cells (Shalek et al., 2014) or organoids, chemical or genetic perturbations (Kumar et al., 2014), and constant microfluidic perfusion. We are also developing in silico approaches that are powered by in-situ cellular tagging techniques. In each instance, we aim to understand the degree to which extracellular environments modulate, and can be used to rationally control, the responses of individual cells or the overall distribution thereof, with an eye toward engineering ensemble responses.