In humans colorectal cancer (CRC) is a significant cause of morbidity and mortality. New treatment options are urgently needed to supplement existing therapies. Replication-competent oncolytic viruses (RCOVs) for the treatment of cancerous tumors in vivo is a relatively new therapeutic modality with great but largely unrealized potential against CRC. In the context of oncolytic virus safety, oncoselectivity is an important criterion. It is at the conceptual intersection of viral replication strategy and tumor cell biology that RCOVs acquire their oncoselectivity, and thus their safety. Every aspect of tumor molecular biology which distinguishes it from normal, non-neoplastic cells is a potential target for exploitation. In the first section of this review we will provide an explanation of some of the successful and widely used strategies for improving oncoselectivity in wild-type viruses to make them more suitable as RCOVs. In the second section we will describe some of the characteristics of CRC biology which can be exploited to provide oncoselectivity against CRC. Throughout the review examples of successfully-engineered RCOVs which embody the approach or strategy under discussion are noted. By showing what has been done, we hope to highlight what is possible and what remains to be done to generate oncoselective RCOVs for use against CRC in humans.