Cigarette smoking is a major prodromal factor for the onset of many adverse health effects that may occur in the short run and is the leading cause of preventable disease, disability, and death in the United States. Moreover, it is well established that chronic smoking is associated with vascular endothelial dysfunction in a causative and dose-dependent manner primarily related to the release of reactive oxygen species (ROS), nicotine, and the induction of oxidative stress (OS)-driven inflammation. Preclinical studies have also shown that nicotine (the principal e-liquid ingredient used in e-cigarettes) can also cause OS, exacerbating cerebral ischemia and secondary brain injury. Likewise, chronic e-Cig vaping could be prodromal to cerebrovascular impairment and promote cerebrovascular conditions favoring stroke onset and worsening post-ischemic brain injury. Therefore, using mouse models is crucial to understand how xenobiotics such as those released by conventional and/or e-cigs can impact the onset and severity of stroke as well as post-stroke recovery. To appropriately model human-like smoking/vaping behavior in mice, however, the exposure to these xenobiotics must be standardized and undertaken in a controlled environment. This chapter describes a well-validated protocol to reproduce standardized chronic tobacco smoke or e-cigarette vape exposure in mice in the setting of a mouse transient ischemic stroke model.