The healthcare system faces various challenges in human immunodeficiency virus 
(HIV) therapy due to resistance to Anti-Retroviral Therapy (ART) as a 
consequence of the evolutionary process. Despite the success of antiretroviral 
drugs like Zidovudine, Zalcitabine, Raltegravir WHO ranks HIV as one of the 
deadliest diseases with a mortality of one million lives in 2016. Thus, there 
emerges an urgency of developing a novel anti-retroviral agent that combat 
resistant HIV strains. The clinical development of ART from a single drug 
regimen to current triple drug combination is very slow. The progression in the 
structural biology of the viral envelope prompted the discovery of novel 
targets, which can be demonstrated a proficient approach for drug design of 
anti-retroviral agents. The current review enlightens the recent updates in the 
structural biology of the viral envelope and focuses on CCR5 as a validated 
target as well as ways to overcome CCR5 resistance. The article also throws 
light on the SAR studies and most prevalent mutations in the receptor for 
designing CCR5 antagonists that can combat HIV-1 infection. To conclude, the 
paper lists diversified scaffolds that are in pipeline by various pharmaceutical 
companies that could provide an aid for developing novel CCR5 antagonists.