Standard treatment of high-grade glioma (HGG) is based on surgery followed by limited field radiotherapy, while the role of chemotherapy is still controversial. Many randomized trials addressing the role of post-radiation or "adjuvant" chemotherapy have been conducted in the last three decades, yielding negative or inconclusive results. A statistically significant survival benefit with adjuvant chemotherapy has been demonstrated in two meta-analyses. The estimated absolute increase in survival is modest (10% at 1 year) but significant, and it appears independent of age, Performance Status and histology. Nitrosourea-based regimens were long considered the standard chemotherapy options for HGG, but their toxicity is not negligible. Temozolomide (TMZ) is a promising new drug that seems to be effective in patients with recurrent disease. Clinically and statistically significant survival benefit with the administration of TMZ concomitant and after radiotherapy has been recently demonstrated, establishing a new standard in HGG adjuvant treatment. Randomized comparisons with nitrosoureas are lacking and represent a major issue to be studied in future phase III trials.