Tissue engineering has progressed to enable development of engineered 3D in vitro tissue models that can recapitulate in vivo cellular physiologies through the control of an expansive variety of microenvironmental design features, including mechanical, extracellular matrix, and soluble stimulatory cues. Microenviromental cues stimulate cells through a system of interconnected molecular regulatory pathways that govern cellular behaviors within engineered tissue models. Detailed understanding of how cell signaling pathways process these microenvironmental stimuli to govern their behaviors will require application of systems-level biological approaches. To date, the experimental and modeling approaches at the heart of systems biology have largely been examined in relatively simple experimental contexts that are readily and repeatedly addressable, such as mammalian cell lines in 2D culture. To enhance the prospects for systems biology to bring about insight into the complex cellular processes underlying human physiology and disease, and to identify and validate candidate therapeutic approaches, it needs to be advanced into improved experimental contexts that more effectively represent the complexity and functionality of native tissues. Herein, we discuss how systems biology can be adapted to the experimental constraints and interests of tissue engineering, and suggest how systems biology could aid in designing and investigating engineered tissue models for the study of human physiology and pathophysiology.