The therapeutic strategy to treat brain metastases depends on the patients’ performance status, systemic tumor activity and the negative impact of older age. Treatment with surgery, radiosurgery and whole brain radiation therapy are the first line therapies for the majority of patients. Although chemotherapy as a single modality has demonstrated limited efficacy, it may improve the result as a concurrent treatment. Overall, there is only limited data on chemotherapeutic protocols from which no firm treatment recommendation can be drawn. Therefore, the chemotherapeutic regimen with highest efficacy to fight the primary tumor in principle is considered also to be the most efficacious for the corresponding brain metastasis. In general, malignant melanoma, renal cell carcinomaand NSCLC show a fairly low chemosensitivity, whereas breast cancer reveal a moderately, SCLC and germ cell cancers a rather high chemosensitivity. The role of TMZ in the treatment of brain metastases is still unclear. Several studies on treating brain metastases with TMZ alone showed low response rates. Preliminary results from randomized trials suggest that combination of TMZ and WBRT is an effective option for patients with brain Epothilone D metastases of non small cell lung cancer. In malignant melanoma, a reduction of mortality from 69% to 41% was observed. For patients with breast cancer and renal cell carcinoma brain metastases, TMZ seems to be less helpful. An obvious possible explanation for variable TMZ efficacy in treating brain metastases is that MGMT promoter methylation has not been investigated systematically in brain metastases. Thus, similarly as for malignant gliomas, where epigenetic silencing of the MGMT gene by promoter methylation has been shown to be of predictive value for profiting from TMZ,Laropiprant TMZ efficacy needs to be correlated to the MGMT promoter methylation status in individual brain metastases. In this study, we show that about one third of brain metastases revealed a methylated MGMT promoter. The methylation rate in the different tumor subgroups ranged between 20% and 46.5%. These results are in line with a previous study on a rather limited number of brain metastases resulting in promoter methylation in,36%. Most studies assessing MGMT promoter methylation status utilize MS-PCR, which is a cost-efficient method requiring only small quantities of DNA. However, DNA derived from FFPEtissue – the routine approach to process tissue for histological assessment and archiving – has been reported to be more often degraded, thus limiting the validity of molecular analyses. On top, bisulfite treatment – a prerequisite for MGMT promoter methylation assays – introduces various additional DNA strand breaks resulting in highly fragmented single stranded DNA. Detection of the MGMT methylation status by 80 cycles of a nested PCR, as recommended for DNA isolated from formalinfixed paraffin-embedded tissue, may easily increase the frequency of sampling error, thus negatively influencing the reliability of results obtained by MS-PCR. This may explain as to why only 61.2% of our samples were evaluable by MS-PCR and why only in 75% of the cases replicate experiments on 20 randomly selected tumor samples yielded reproducible results.