In the past decade, microphysiological systems or organs-on-a-chip systems (organ chips) have attracted increasing attention because they can provide human organ-like in vitro models. Human organs are complex networks and contain physical (matrix micro/nanostructures and stiffness), mechanical (fluidic forces and mechanical stimuli) and biochemical (such as growth factors and cytokines) cues. These cues critically influence numerous developmental, physiological and pathological processes in vivo, and have been applied to modulate almost all aspects of cell behavior in vitro. Yet these cues have not been fully implemented in the development of organ chips. By taking biomaterials and polymer micro-/nanoengineering approaches, we are able to engineer biomimetic organ chips that recapitulate the key anatomical and physiological characteristics of human organs. We have engineered a three-dimensional (3-D) tumor chip with controlled cell-cell and cell-matrix interactions for chemoresistance study of acute lymphoblastic leukemia. To develop a lung alveolar interstitium model, we have investigated the effects of interstitial nanostructures and stiffness on cellular responses to engineered nanomaterials. We have further developed microfluidic platforms which enable 2-D and 3-D mechanical stretches to mimic blood pressure-induced circumferential stretch and breathing movement, respectively. Therefore, we are able to integrate the interstitial nanostructures and stiffness cues with the 3-D breathing movement in a biomimetic lung alveolar interstitium chip for nanotoxicology study. With the enabling technique, we have been developing blood-brain barrier/blood-tumor barrier (BBB/BTB) chips and an optic nerve head chip. The engineered biomimetic organ chips are expected to advance our understanding and treatment of human disease.