Evasion　of　growth　suppression　is　among　the　prominent　hallmarks　of　cancer.　Phosphatase　and　tensin　homolog　(PTEN)　and　p53　tumor-suppressive　pathways　are　compromised　in　most　human　cancers,　including　glioblastoma　(GB).　Hence,　these　signaling　pathways　are　an　ideal　point　of　focus　for　novel　cancer　therapeutics.　Recombinant　viruses　can　selectivity　kill　cancer　cells　and　carry　therapeutic　genes　to　tumors.　Specifically,　oncolytic　viruses　(OV)　have　been　successfully　employed　for　gene　delivery　in　GB　animal　models　and　showed　potential　to　neutralize　immunosuppression　at　the　tumor　site.　However,　the　associated　systemic　immunogenicity,　inefficient　transduction　of　GB　cells,　and　inadequate　distribution　to　metastatic　tumors　have　been　the　major　bottlenecks　in　clinical　studies.　Mesenchymal　stem　cells　(MSCs),　with　tumor-tropic　properties　and　immune　privilege,　can　improve　OVs　targeting.　Remarkably,　combining　the　two　approaches　can　address　their　individual　issues.　Herein,　we　summarize　findings　to　advocate　the　reactivation　of　tumor　suppressors　p53　and　PTEN　in　GB　treatment　and　use　MSCs　as　a　＂Trojan　horse＂　to　carry　oncolytic　viral　cargo　to　disseminated　tumor　beds.　The　integration　of　MSCs　and　OVs　can　emerge　as　the　new　paradigm　in　cancer　treatment.