Personalized medicine for cancer entails tailoring therapy for each patient based on unique features of the patient's tumor; physiologic, molecular, genetic and epigenetic. Our ability to molecularly characterize tumor cells has increased dramatically and shown that there are significant differences between samples from patients with the same tumor type. Given this extensive variability in mutations and pathways driving tumors in patients, seeking a single bullet is an unrealistic approach for achieving a cure. In glioblastoma multiforme (GBM), the most common adult brain tumor, this inter-tumoral heterogeneity is further complicated by intra-tumoral heterogeneity within the tumor. This suggests that for personalized therapy to work for GBMs, pharmacologic agents would not only be tailored to target the differences from patient to patient but also the clonal diversity within each patient's tumor. In this review, we provide a historical perspective on clinical trials for cancer. We also discuss the current state of molecular biology and immunology based strategies for personalized therapies for glioblastoma multiforme.