Background: The infectious human immunodeficiency virus (HIV) particle is characterized by a conical capsid that encloses the viral RNA genome. The capsid is essential for HIV-1 replication and plays crucial roles in both early and late stages of the viral life cycle. Early on, upon fusion of the viral and cellular membranes, the viral capsid is released into the host cell cytoplasm and dissociates in a process known as uncoating, tightly associated with the reverse transcription of the viral genome. During the late stages of viral replication, the Gag polyprotein, precursor of the capsid protein, assemble at the plasma membrane to form immature non-infectious viral particles. After a maturation step by the viral protease, the capsid assembles to form a fullerene-like conical shape characteristic of the mature infectious particle. Mutations affecting the uncoating process, or capsid assembly and maturation, have been shown to hamper viral infectivity. The key role of capsid in viral replication and the absence of approved drugs against this protein have promoted the development of antiretrovirals. Screening based on the inhibition of capsid assembly and virtual screening for molecules binding to the capsid have successfully identified a number of potential small molecule compounds. Unfortunately, none of these molecules is currently used in the clinic. Conclusion: Here we review the discovery and the mechanism of action of the small molecules and peptides identified as capsid inhibitors, and discuss their therapeutic potential.