Interspecies differences, anatomical and physiological aspects, as wells as simplified study designs contribute to an overestimation of treatment effects and limit the transferability of experimental results into clinical applications. Confounders of cell therapies for cerebrovascular disorders (CVD) include common CVD comorbidities, frequent medications potentially affecting endogenous and transplanted stem cells, as well as age- and immune-system-related effects. All those can contribute to a substantial modeling bias, ultimately limiting the prospective quality of preclinical research programs regarding the clinical value of a particular cell therapy. In this review, we discuss the nature and impact of most relevant confounders. We provide suggestions on how they can be considered to enhance the validity of CVD models in stem cell research. Acknowledging substantial and sometimes surprising effects of housing conditions, chronobiology, and intersex differences will further augment the translational value of animal models. We finally discuss options for the implementation of high-quality functional and imaging readout protocols. Altogether, this might help to gain a more holistic picture about the therapeutic impact of a particular cell therapy for CVD, but also on potential side and off-site effects of the intervention. Stem Cells2017;35:1141-1153