The prevalence of HIV-infected people aged 50 years or older is increasing rapidly and this population often exhibits a higher number of comorbidities and other age-related conditions at a younger age than in the general population. Numerous cohort studies (eg NA-Accord, EuroSIDA, DatAIDS, GEPPO, PODIVM, MACS, US Veterans Affairs, POPPY; SHCS) have highlighted the increasing burden of co-morbidities in older PLWH with some studies describing the prevalence of polypharmacy (most often described as more than 5 co-medications) to be >40%. With polypharmacy comes the inevitable consideration of drug-drug interactions (DDIs). So we need to understand i) the mechanisms of DDIs (which are not always CYP-mediated!), ii) the difference in DDI potential of the currently recommended antiretroviral agents and iii) the clinical relevance of DDIs. We always need to be aware of the unexpected! The prescribing information or label of a drug is often the primary source of DDI awareness. But the labels cover a limited number of specific DDIs and not infrequently there are differences between the US Prescribing Information and the European SmPC or country specific information which may confuse. Therefore health care professionals often rely on other sources (websites, apps) for their daily management of DDIs. With commonly used co-medications it may be necessary to: change or modify the dose of a co-medication, change the ARV, modify the dose of the ARV or take care with the timing of administration. However it is also important to take care that co-meds are not under dosed. As we look to the future, we need research programs to determine the impact of eliminating medications not essential for quality of life and survival for those aging with HIV (ie de-prescribing). We also need to face the challenge of DDI studies with long acting ARVs – currently injectable and implants. However there are other emerging technologies and with all long acting medicines there will be an important role for PBPK modelling in generating DDI data in virtual patients.