Too controversial to discuss only a short time ago, achieving a cure for HIV infection has become a priority in HIV research. However, substantial challenges must be overcome. Among key hurdles to be surmounted is the definition of a reliable, validated model in which to test latency reversal agents (LRAs), as current primary cell models differ in their response to such agents. Animal models such as the HIV-infected humanized BLT mouse and SIV-infected macaque will be essential to study LRAs and to quantify their effects in anatomic reservoirs. Of several potential anatomic reservoirs, the central nervous system presents a significant obstacle, as it is known to harbor persistent HIV infection and is difficult to access for study and therapeutic intervention.