Definitive treatment of cancer has eluded scientists for decades. Current therapeutic modalities like surgery, chemotherapy, radiotherapy and receptor-targeted antibodies have varied degree of success and generally have moderate to severe side effects. Gene therapy is one of the novel and promising approaches for therapeutic intervention of cancer. Viral vectors in general and adenoviral (Ad) vectors in particular are efficient natural gene delivery systems and are one of the obvious choices for cancer gene therapy. Clinical and preclinical findings with a wide variety of approaches like tumor suppressor and suicide gene therapy, oncolysis, immunotherapy, anti-angiogenesis and RNA interference using Ad vectors have been quite promising, but there are still many hurdles to overcome. Shortcomings like increased immunogenicity, prevalence of preexisting anti-Ad immunity in human population and lack of specific targeting limit the clinical usefulness of Ad vectors. In recent years, extensive research efforts have been made to overcome these limitations through a variety of approaches including the use of conditionally-replicating Ad and specific targeting of tumor cells. In this review, we discuss the potential strengths and limitations of Ad vectors for cancer therapy.