Microvascular dysfunction is associated with the pathophysiology of many diseases, such as sickle cell disease. However, due to the small size scale and its location deep inside the tissues, the pathological events that occur in the microvasculature are commonly invisible under the clinical settings and difficult to study using animal models as well. Therefore, the underlying mechanisms of microvascular dysfunction in disease are poorly understood. To address this challenge, we are developing novel hydrogel-based microvasculature-on-chips by harnessing microfabrication and material science to model microvasculature with long-term physiologically relevant properties, which allows us to recapitulate and monitor the pathological events of microvascular dysfunction in disease with high resolution. Here I will present the development of the hydrogel-based microvasculature-on-chip system and our recent progress in using this novel system to study the microvascular occlusion and test the therapeutics in sickle cell disease.