Glioblastoma (GBM) is a lethal form of primary brain tumor in human adults. The impact of tumor-intrinsic alterations is not exclusively confined to cancer cells but can also be extended to the tumor microenvironment (TME). Glioblastoma-associated macrophages/microglia (GAMs) are a prominent type of immune cells that account for up to 50% of total cells in GBM. Emerging evidence suggests that context-dependent GBM–GAM symbiotic interactions are pivotal for tumor growth and progression. Here, we discuss how specific genetic alterations in GBM cells affect GAM biology and, reciprocally, how GAMs support GBM progression. We hypothesize that understanding context-dependent GBM–GAM symbiosis may reveal the molecular basis of GBM tumorigenesis and lead to novel candidate treatment approaches aiming to improve GBM patient outcomes.