Promising preclinical and clinical data led to the initiation of an international randomised phase II/III trial of p53 gene-therapy trial for first-line treatment of patients with ovarian cancer. In that trial, replication-deficient adenoviral vectors carrying wild-type p53 were given intraperitoneally in combination with standard chemotherapy to patients with ovarian cancers harbouring p53 mutations. The study was closed after the first interim analysis because an adequate therapeutic benefit was not shown. In this review, we discuss the possible reasons for failure of p53 gene therapy, which include the multiple genetic changes in cancer and epigenetic dysregulations leading to aberrant silencing of genes. These complex interactions lead us to conclude that repair of single genes might not be a suitable strategy for the treatment of cancer. Moreover, dominant negative cross talk between ectopic wild-type p53 and recently identified dominant p53 mutants and splice variants of p63 and p73— which are frequently overexpressed in ovarian cancers— could seriously compromise the effectiveness of p53 gene therapy. Other substantial problems in targeting tumour cells with adenoviral vectors are the heterogeneity or lack of expression of coxsackie-adenovirus receptors and integrin co-receptors in ovarian tumours and the presence of adenovirus-neutralising antibodies in ovarian cancer-related ascites.