Disruption of cellular functions with aging-induced accumulation of neuronal stressors causes cell death which is a common feature of neurodegenerative diseases. Studies in a variety of neurodegenerative disease models demonstrate that poly (ADP-ribose) (PAR)-dependent cell death, also named parthanatos, is responsible for neuronal loss in neurological diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). Parthanatos has distinct features that differ from caspase-dependent apoptosis, necrosis or autophagic cell death. Parthanatos can be triggered by the accumulation of PAR due to overactivation of PAR polymerase-1 (PARP-1). Excess PAR, induces the mitochondrial release apoptosis-inducing factor (AIF), which binds to macrophage migration inhibitory factor (MIF) carrying MIF into the nucleus where it cleaves genomic DNA into large fragments. In this review, we will discuss the molecular mechanisms of parthanatos and their role in neurodegenerative diseases. Furthermore, we will discuss promising therapeutic interventions within the pathological PAR signaling cascade that could be designed to halt the progression of neurodegeneration.