Peripheral arterial disease (PAD) is a global health issue that is becoming more prevalent in an aging world population. Diabetes mellitus and chronic kidney disease are also on the increase, and both are associated with accelerated vascular calcification and an unfavorable prognosis in PAD. These data challenge the traditional athero-centric view of PAD, instead pointing toward a disease process complicated by medial arterial calcification. Like atherosclerosis, aging is a potent risk factor for medial arterial calcification, and accelerated vascular aging may underpin the devastating manifestations of PAD, particularly in patients prone to calcification. Consequently, this review will attempt to dissect the relationship between medial arterial calcification and atherosclerosis in PAD and identify common as well as novel risk factors that may contribute to and accelerate progression of PAD. In this context, we focus on the complex interplay between oxidative stress, DNA damage, and vascular aging, as well as the unexplored role of neuropathy.