Glioblastoma is difficult to treat and patients are often provided poor prognosis (1), indicating a requirement for therapeutic target identification and drug development. Differentially expressed genes represent by definition among the most promising targets for the development of novel chemotherapies (2, 3). We predict therapeutic index is intrinsically linked to differential expression which can be comprehensively and blindly determined using whole transcriptome data, further limiting toxicity by design (4). We mined published and public microarray and RNA-sequencing data (5, 6) to identify differentially expressed gene products in glioblastoma by performing whole transcriptome gene expression profiling. We found that the gene encoding the atypical chemokine receptor 3, ACKR3, was among those whose expression was most different in human glioblastoma tumors when comparing total transcription between tumor and normal brain tissue. ACKR3 expression levels were significantly increased in glioblastoma tumors as compared to the non-transformed brain. ACKR3 function at the systems level was assessed by studying whole transcriptome transcriptional co-regulation in the transformed brain. ACKR3 is a target of interest for the treatment of glioblastoma, as part of a rationally designed chemotherapeutic regimen that utilizes gene expression data from patient tumors and healthy non-transformed tissues to maximize efficacy and safety and minimize toxicity.