In recent years, oncolytic viruses have been genetically engineered to target cancer cells selectively. Adenovirus is one such oncolytic virus that is being tested in clinical trials for the treatment of cancer. The observation that cells infected with replication-competent adenoviruses undergo autophagy has provided new options for investigating the mechanism of adenovirus-induced cell death. It has been suggested that the use of autophagy inducers, such as rapamycin, can enhance the oncolytic potency of recombinant adenoviruses. Additionally, several research groups have established that inserting microRNA (miRNA)-targeted sequences into the adenoviral genome can modulate adenoviral protein expression to confer tissue and tumor selectivity. Furthermore, the capability of adenoviruses to inhibit the expression of the DNA repair enzyme MGMT and to chemosensitize glioma cells to temozolomide has been demonstrated. This review discusses three aspects of the use of oncolytic adenoviruses to treat cancer: (i) the induction of autophagy and autophagic cell death during adenoviral replication; (ii) the opportunities and strategies involved in the exploitation of miRNA specificity to generate tissue- and tumor-selective oncolytic viruses; and (iii) the rationale for combining oncolytic adenoviruses with chemotherapeutic agents.