Vascular nitric oxide (NO•) resistance, manifested by an impaired vasodilator function of NO• in both the macro- and microvessels, is a common state in type 2 diabetes (T2D) associated with developing cardiovascular events and death. Here, we summarize experimental and human evidence of vascular NO• resistance in T2D and discuss its underlying mechanisms. Human studies indicate a ~ 13-94% decrease in the endothelium (ET)-dependent vascular smooth muscle (VSM) relaxation and a 6-42% reduced response to NO• donors, i.e., sodium nitroprusside (SNP) and glyceryl trinitrate (GTN), in patients with T2D. A decreased vascular NO• production, NO• inactivation, and impaired responsiveness of VSM to NO• [occurred due to quenching NO• activity, desensitization of its receptor soluble guanylate cyclase (sGC), and/or impairment of its downstream pathway, cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG)] are the known mechanisms underlying the vascular NO• resistance in T2D. Hyperglycemia-induced overproduction of reactive oxygen species (ROS) and vascular insulin resistance are key players in this state. Therefore, upregulating vascular NO• availability, re-sensitizing or bypassing the non-responsive pathways to NO•, and targeting key vascular sources of ROS production may be clinically relevant pharmacological approaches to circumvent T2D-induced vascular NO• resistance.