Tetrahydro-β-carbolines (THβCs) and β-carbolines (βCs) are bioactive naturally occurring indole alkaloids and structural analogs of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridinium (MPP+) Parkinsonian neurotoxins. Humans are daily exposed to these compounds through the diet, smoking, and plants, and they are also found endogenously in human tissues and brain. βCs can be converted by N-methyltransferases occurring in the mammalian brain into N-methyl-β-carbolinium cations (βC+s) which are neurotoxins. These βC cations have been detected in the human brain and share with MPP+ several toxicological features such as inhibition of mitochondrial complex I, increase of ROS production and induction of cell apoptosis. As a result, they produce neurotoxicity in vitro and in vivo. Among βC cations, the most potent neurotoxins are N,N-dimethylated βC cations (2,9-diMe-βC+s) that are produced from sequential N-methylation of βCs at the N-2 (pyrido) and N-9 (indole) nitrogens. Toxicity of 2,9-diMe-βC+s approaches that of MPP+ although it is less selective for dopaminergic cells. THβCs and βCs are metabolized by several cytochrome P450 enzymes to hydroxylated derivatives in a detoxification process that may compete with their bioactivation to neurotoxins by N-methyltransferases. Alternatively, N-methylTHβCs could be also bioactivated to aromatic βCs by heme peroxidases. These metabolic features affect the toxicological outcome of these compounds. Taken together, THβCs and βCs could be potential environmental and endogenous proneurotoxins that after bioactivation might play a role in the pathogenesis of neurodegenerative diseases in susceptible individuals. In the future, new studies are needed to clarify if the physiological levels of THβCs and βCs that reach and accumulate in the human brain may induce significant neurotoxicity in the sort and/or long-term or in contrast they may exert alternatively other bioactive actions including neuroprotection.