HIV infection of two key immune cells, CD4+ T cells and macrophages, plays a major role in the establishment of HIV infection and the seeding of the latent reservoir. There is a critical gap in our understanding of the determinants of viral tropism for these cell types and the molecular Env-receptor interactions involved. The development of novel futuristic methods including machine learning and neural network approaches, will allow the generation of sophisticated genotypic predication algorithms which will greatly enhance accurate HIV coreceptor usage identification within the clinic. Furthermore, advancements in surface plasmon resonance, biolayer interferometry and glycol-FRET technologies will be fundamental for real time investigation of molecular mechanisms involvement in Env-receptor interactions, which will enhance our understanding of coreceptor usage and viral tropism determinants. These technologies will be important for the development and improvement of therapeutic efficacy, novel entry inhibitors and assist vaccine design.