Malignant endocrine tumors are relatively rare, but they may cause significant morbidity and mortality. Metastatic disease is not generally amenable to surgery, chemotherapy, or radiotherapy. There is therefore great interest in developing gene therapy as a treatment for metastases and for some primary endocrine tumors. Current gene therapy strategies largely involve the use of gene-directed enzyme pro-drug therapy (GDEPT) and using recombinant adenovirus vectors. In this review the authors examine the basic strategies used in GDEPT, progress in this area, and future directions of this work.