In the last decade, the design of artificial organelles and cells has emerged as an area with far‐reaching implications due to the potential that such systems have for both understanding bioprocesses in a simple and controlled manner, and for developing advanced solutions for medical applications. Significant efforts have been devoted to developing artificial organelles and cells as single compartments or compartments‐in‐compartments to enable the study of internal reactions. However, a major challenge in approaching natural processes is to be able to mimic complex signaling and communication pathways. In this review, we present bottom‐up strategies that introduce polymer‐based protocells for studying intra‐ and intercellular communication. Whereas intracellular communication involves in situ reactions that are triggered by an external stimulus, intercellular communication is achieved by exchange of chemical signals between two different types of protocell, the “sender” and “receiver.” By spatially segregating different molecules and nano‐assemblies that serve as artificial organelles in sender and receiver protocells, respectively, various reactions have been studied, including single and cascade enzymatic reactions. Such interconnected systems, which facilitate exchange and flow of information in a close‐to‐nature manner, increase our insight into complex natural signaling pathways and hold promise for creation of programmable artificial cell‐ and tissue‐like systems for tomorrow's medicine.