I use precision biomaterial platforms to probe valvular fibroblast activation. Aortic valve stenosis (AVS) is a progressive disease characterized by aberrant stiffening of the aortic valve, leading to inadequate blood flow from the left ventricle and eventual heart failure. AVS is currently treated exclusively with valve replacement surgeries, which may be avoided if effective small molecule therapeutics could be identified to slow or reverse AVS progression. During AVS progression, a large fraction of valvular interstitial cells (VICs) differentiate into pathogenically activated myofibroblasts, which contribute to excessive matrix deposition and eventual valve leaflet stiffening. Effective small molecule therapeutics intended to reverse myofibroblast activation remain elusive, owing to the inherent heterogeneity of the cellular microenvironment from patient to patient. For example, male patients show increased calcification and female patients show increased tissue fibrosis in the aortic valve microenvironment, leading to differential drug responses. Considering these clinical observations, we seek to engineer precision biomaterial microenvironments to recapitulate patient-specific AVS progression in vitro and identify molecular mechanisms that mediate reversal of myofibroblast activation. Precision biomaterials are defined as engineered environments that enable the evaluation of how patient-specific variables may influence disease progression. As a strategy to evaluate patient-specific AVS progression, we utilize poly(ethylene glycol) (PEG) hydrogels as precision in vitro platforms to probe various biochemical and mechanical cues that activate VICs to a myofibroblast state, as well as cues that reverse activation. Our work demonstrates how engineered hydrogel matrices enable an increased understanding of the molecular mechanisms guiding myofibroblast activation and reversal, which may provide a critical bridge toward patient-specific small molecule AVS therapies.