Mefloquine, a potent anti-malarial therapeutic, is known to cause adverse neurological or psychiatric effects in a subset of patient population which has been reportedly linked with specific single nucleotide polymorphisms (SNPs). Development of a predictive clinical, molecular diagnostic screen capable for the a priori determination of the susceptibility of an individual to Mefloquine neurotoxicity is critical for safe administration. Towards achieving this goal, we present a novel systems-biology centered methodology, combining transcriptional profiling using primary rat cortical neurons exposed to Mefloquine and novel pathway identification/analysis tools enabling the development of a detailed intracellular pathway model to explain Mefloquine-induced neurotoxicity. Boolean methods are used to objectively down select potential SNP target candidates. The results from the proposed methodology have consistently identified PTK2B as the most likely SNP target across multiple data sets, and using multiple toxicity markers.