Interest and studies focused on the role of immune and inflammatory mechanisms in vascular disease have advanced in synchrony with the advances in the understanding of innate immune system regulation and the interplay between innate and adaptive immunity. Clinical studies have implicated immune and inflammatory mechanisms in stroke and acute coronary syndromes. Analyses of genetically modified mice and in vitro and in vivo preclinical ischemia models have yielded insights into pathobiological mechanisms. Deciphering the role of innate immune mechanisms that confer tolerance to ischemia might guide translation of more effective therapies. Antigen-targeted and other forms of focused immunomodulation that can suppress vessel activation and protect ischemic tissue might ultimately find a niche in the prevention and treatment of vascular disease.