Oncolytic virotherapy is a rapidly progressing field that uses oncolytic viruses (OVs) to selectively infect malignant cells and cause an antitumor response through direct oncolysis and stimulation of the immune system. Despite demonstrated pre-clinical efficacy of OVs in many cancer types and some favorable clinical results in glioblastoma (GBM) trials, durable increases in over-all survival have remained elusive. Recent evidence has emerged that tumor-associated macro-phage/microglia (TAM) involvement is likely an important factor contributing to OV treatment fail-ure. It is prudent to note that the relationship between TAMs and OV therapy failures is complex. Canonically activated TAMs (i.e., M1) drive an antitumor response while also inhibiting OV replication and spread. Meanwhile, M2 activated TAMs facilitate an immunosuppressive microenviron-ment thereby indirectly promoting tumor growth. In this focused review, we discuss the compli-cated interplay between TAMs and OV therapies in GBM. We review past studies that aimed to maximize effectiveness through immune system modulation—both immunostimulatory and im-munosuppressant—and suggest future directions to maximize OV efficacy.