Stroke research continues to face many challenges as we struggle to overcome translational hurdles between basic science and clinical applications. To date, the only established therapy is thrombolytic reperfusion, whereas numerous trials of pure neuroprotection have not yielded clear efficacy. In this presentation, we will assess the hypothesis that effective translational research must be based on mechanisms, and that linked platforms of cell-to-tissue-to-whole-animal models are required. Protease mechanisms that underlie cell-cell and cell-matrix signaling at the neurovascular interface will be examined as a case study of how acute injury is inextricably linked to delayed remodeling. Some complications of tPA reperfusion may be associated with dysregulation of matrix metalloproteinase (MMP) networks. Degradation of neurovascular matrix may underlie BBB injury, edema, hemorrhage and cell death. In contrast, brain tissue remodeling and neurogenesis may in turn be dependent on regulated MMP processes during stroke recovery. MMP and inflammatory responses at both tissue and biomarker levels will be assessed as an example of how analysis at multiple cell levels may provide information useful for interpretation of animal model systems. Attention to neurovascular mechanisms at molecular, cellular and organ levels of analysis may yet provide new opportunities for translating our basic science into meaningful clinical therapies.