Apoptosis is a common mode of cell death that contributes to neuronal loss associated with neurodegeneration. Single-nucleotide polymorphisms (SNPs) in chromosomal DNA are contributing factors dictating natural susceptibility of humans to disease. Here, the most common SNPs affecting neuronal vulnerability to apoptosis are reviewed in the context of neurological disorders. Polymorphic variants in genes encoding apoptotic proteins, either from the extrinsic (FAS, TNF-α, CASP8) or the intrinsic (BAX, BCL2, CASP3, CASP9) pathways could be highly valuable in the diagnosis of neurodegenerative diseases and stroke. Interestingly, the Arg72Pro SNP in TP53, the gene encoding tumor suppressor p53, was recently revealed a biomarker of poor prognosis in stroke due to its ability to modulate neuronal apoptotic death. Search for new SNPs responsible for genetic variability to apoptosis will ensure the implementation of novel diagnostic and prognostic tools, as well as therapeutic strategies against neurological diseases.