The basal ganglia (BG) include structures pivotal for motor and cognitive functions. Such structures are affected in neurodegenerative disorders and toxic or ischemic insults. The peculiar vulnerability of BG to toxic and ischemic damage has been the focus of preclinical research for all over the last century. This comprehensive review collects all evidences supporting a specific susceptibility of BG to energy deprivation, highlighting the pathways through which neuronal survival is jeopardized, and the consequent clinical correlates. In particular, we addressed intrinsic and extrinsic factors participating in BG neuronal vulnerability. The terminal blood supply, the main extrinsic factor, is crucial to the low threshold for hypoxic hazard. Specific, the lack of anastomoses between second and third order branches represents the frailty of an archaic terminal network, unable to guarantee collateral supply and resistance to oxygen deprivation. In addition, BG neurons survival is jeopardized by several intrinsic molecular factors. Among them, the subunit composition of ionotropic and metabotropic glutamate receptors, the impairment of mitochondria, the deficit in neurotransmitter clearance, the poor control of intracellular calcium homeostasis and the glutamatergic-dopaminergic pro-excitotoxic interplay, all play a significant role. Intrinsic and extrinsic factors represent two faces of the same coin, producing excitotoxic damage and poor ability to deal with energy deprivation. The clinical correlates of BG vulnerability are represented by ischemic lesions, such as striatocapsular infarcts and lacunar infarcts, and local toxic-induced damage, mainly associated with energy production impairment, due to carbon monoxide, cyanide and manganese.