•Integrase (IN), an essential HIV-1 enzyme, is an important therapeutic target.•Allosteric IN inhibitors (ALLINIs) are an emerging class of anti-HIV drug.•ALLINIs promote IN dimerization and block IN–viral DNA assembly and IN catalysis.•ALLINIs display steep dose response curve slopes ex vivo.•ALLINIs synergize with strand transfer inhibitors that target the IN active site. HIV-1 integrase is an important therapeutic target in the fight against HIV/AIDS. Integrase strand transfer inhibitors (INSTIs), which target the enzyme active site, have witnessed clinical success over the past 5 years, but the generation of drug resistance poses challenges to INSTI-based therapies moving forward. Integrase is a dynamic protein, and its ordered multimerization is critical to enzyme activity. The integrase tetramer, bound to viral DNA, interacts with host LEDGF/p75 protein to tether integration to active genes. Allosteric integrase inhibitors (ALLINIs) that compete with LEDGF/p75 for binding to integrase disrupt integrase assembly with viral DNA and allosterically inhibit enzyme function. ALLINIs display steep dose response curves and synergize with INSTIs ex vivo, highlighting this novel inhibitor class for clinical development.