From the prehistoric time man has always struggle to fight and control diseases and motivated to nature for inspiration and guidance. During thousands of years of early human existence, number of natural materials by instinct or intuition has been used as folk medicines for human ailments. This brought to the forefront a large number of herbs used in Indian indigenous system for their approved efficiency and administration in modern medicines. Acquired immunodeficiency syndrome (AIDS) caused by human immunodeficiency virus (HIV) is an immuno-suppressive disease that results in life-threatening opportunistic infections and malignancies. Now, there is an urgent need for novel anti-HIV/AIDS drugs for global concern. In addition to obvious economical and commercial obstacles, HIV/AIDS patients are faced with varied difficulties associated with the currently approved anti-HIV drugs. The therapeutic usefulness of the various reverse transcriptase and protease inhibitors available in the market have been limited due to its adverse effect, emerging drug resistance and low activity. This encourages many scientists to look for new antiretrovirals with better efficacy, safety and affordability. Several natural products isolated from plants have been shown to possess promising activities that could assist in the prevention and/or amelioration of the disease. Biodiversity of the plant kingdom has always been a source of new drug candidates for various diseases. The appearance of drug resistant virus urged the scientists to explore new anti-HIV agents and targets. In this regard, natural products embody a treasure-trove of anti-HIV drugs waiting to be explored by all the modern techniques. Numerous natural product based anti-HIV drugs such as Robustaflavone, Chamaeflavone A, Longipedunins A, Binankadsurin A, Schisanlactone A, Anibamine, Altertoxine, Betulinic acid, Baicalin, Hinokiflavone, etc., have been reported in the literature which possess promising anti-HIV activity. This chapter embodies the recent progress that has been accomplished in the discovery of promising anti-HIV agents from natural sources.