Measles vaccine virus (MeV) has been shown to possess profound oncolytic capabilities. However, tumor cell resistance to MeV may endanger broad clinical success. Here, this hypothesis is underlined by our analysis of the NCI-60 tumor cell panel infected with a suicide gene-armed MeV vector (MeV-SCD). Quantification of the MeV-SCD-induced oncolytic effect exhibited a 50% rate of NCI-60 solid tumor cell lines being susceptible to MeV-SCD induced oncolysis. In contrast, nearly 40% of the NCI-60 tumor cell lines had to be categorized as partially resistant (exhibiting 50-75% remnant tumor cells) and six tumor cell lines even showed high resistance to MeV-SCD-induced oncolysis with remnant tumor cell masses >75%. According to our further analysis, these high-grade resistant tumor cell lines i) exhibited a high variation in primary infectability rates and also different patterns of alterations ii) in virus replication and iii) in interferon response. This diversity of virotherapy resistance phenomena seems to go along with the diversity of genetic and epigenetic changes accompanying malignant transformation. Of paramount clinical importance, this plethora of resistance phenomena was shown to be overcome in vitro by employment of an increased MOI together with addition of the prodrug 5-FC, thus exploiting the highly efficient suicide gene function of vector MeV-SCD used in this study.