<p>Glioblastoma multiforme (GBM) is an extremely aggressive brain tumor characterized by rapid progression, poor prognosis, and limited potential for remission. A contributing factor to the aggressiveness of GBM is the high genetic and phenotypic variability of the tumor caused by the accumulation of beneficial mutations over time. Screening methodologies utilizing genetic tools such as clustered regulatory interspaced short palindromic repeats (CRISPR) and ribonucleic acid (RNA) interference (RNAi) have proven effective in identifying oncogenic driver genes in GBM. Here, we analyze and summarize these studies. Analysis of hits emerging from genetic screens in GBM has revealed key factors with the capacity for regulating deoxyribonucleic acid (DNA) repair, cell cycle, or metabolism of the cancer. The genetic programs which endow GBM a high degree of aggressiveness also contribute to outcompeting immune cells associated with tumor cell clearance. Genes identified in genetic screens influence the receptor landscape on the surface of both GBM and immune cells, as well as the soluble factors within the tumor microenvironment (TME). These soluble factors and surface receptors regulate function of immune cells, in particular natural killer (NK) cells. This systematic review links genetic drivers of GBM identified through screening approaches and their documented roles. As will be discussed, these genes were shown in literature to encode molecular programs that confer a competitive advantage to GBM in contexts such as chemotherapy and radiotherapy.</p>