Background: HIV/AIDS remains a major global public health challenge despite significant progress in treatment. New infections and HIV-related deaths persist, fueled by disparities in prevention and care access. Purpose: This review synthesizes recent advances across key domains - from vaccine development to novel treatments to omics approaches – that collectively hold promise for ending the HIV/AIDS pandemic. Main body: Multiple innovative HIV vaccine platforms are now in early-phase trials, including mRNA vaccines as well as conserved epitope and mosaic constructs for broader immunogenicity. Long-acting injectable antiretrovirals represent a major milestone in HIV treatment, while gene editing techniques offer future curative potential. Leveraging multi-omics data through genomics, transcriptomics, proteomics, and metabolomics provides systems-level insights into viral persistence and new therapeutic opportunities. The gut microbiome is increasingly recognized as a mediator of HIV progression, spurring research into probiotic/prebiotic supplementation and fecal transplantation. Across these domains, integration of artificial intelligence and machine learning will likely accelerate discovery. Conclusion: Despite past setbacks, the HIV cure effort has renewed momentum. Translating emerging tools like long-acting antiretrovirals and omics profiling into broader clinical application could bend the pandemic’s trajectory. Innovation must be paired with ensuring equitable access to maximize global impact.