Cells are products of their environment; thus they are tasked with continuously sensing and interpreting the myriad of signals around them to make decisions that shape their fate. A central principle in research and therapeutic development is precisely controlling and administering such signals, while also maintaining this unique environment, to study cellular responses or achieve desired cell fates. Traditionally these cues have been studied in a unidimensional fashion, which fails to capture the inherent spatiotemporal complexity that carries additional layers of relevant cellular information. Current approaches for enabling dynamic control over cellular systems often rely on genetic perturbations or creating complex synthetic scaffolds to support cell growth, which ultimately limit their widespread application. Here we utilize a number of bio-orthogonal chemistries and rational protein design to shape the extracellular environment in ways that relay controllable and biologically-relevant signals while simultaneously preserving the natural complexity experienced by cells in vivo. This work highlights a cornerstone in molecular tool development by placing an emphasis on strategies that function without the need for prior cellular modifications by working entirely in the extracellular environment. We hope that the ability to control dynamic processes in unmodified cell types, coupled with their approachable nature, will promote the widespread adaptation of these technologies and offer promising routes for advancing therapeutic development.