Twenty-five years after the emergence of HIV onto the global scene, multiple advancements have been made in the understanding of HIV pathology. Thanks to the development of antiretroviral therapies, growing numbers of individuals with HIV infection experience slowed or halted acceleration to AIDS. Despite this, new HIV infections and AIDS-related morbidity and mortality are still common in the highly active antiretroviral therapy era. Recently, we and others have identified viral replicative fitness as a major determinant of HIV disease progression, which could have a major impact in the clinical setting. Therefore, in this review, we will discuss host and viral factors that affect viral fitness and its relationship on HIV pathogenesis.