Chemokines are critical components of the immune system that participate in immune homeostasis and alterations in chemokine balance can result in severe inflammatory and autoimmune diseases. The role of chemokines and their receptors in viral infections including HIV-1 was predicted from the early studies of HIV-1 co-receptor CCR5 and its ligands and a divergent role of C-C chemokines in HIV-1 pathogenesis has been established. For example, CCL3 (MIP-1α), CCL4 (MIP-1β) and CCL5 (RANTES) have been shown to possess antiviral effects by binding to the HIV-1 co-receptor CCR5, whereas CCL2, a pro-inflammatory chemokine, supports HIV-1 replication despite being a member of same chemokine family. Furthermore, the well-established role of CCL2 in driving the Th2 immune response supports its potential role in HIV-1/AIDS. Recent reports suggest multiple pathways of CCL2 affect HIV-1 infection. In this review, we provide a comprehensive overview of the role and potential mechanisms of the HIV-1-CCL2 interplay in driving virus-induced immuno-pathology, suggesting that CCL2 could be an anti-inflammatory target in the treatment of HIV-1 infection.