U=U, the concept that a person with an undetectable viral load is incapable of transmitting HIV sexually, has transformed the lives of people living with HIV worldwide and is doing much to reduce the stigma associated with this condition (although there is still a long way to go). Evidence for U=U comes from clinical trials involving thousands of couples (both homosexual and heterosexual) in serodifferent relationships in which no linked transmissions occurred from HIV-positive people with fully suppressed viral loads. Clinically, however, the practical implementation of U=U in some circumstances may pose a significant challenge; for example, -,Can a clinician discussing the risk of transmission with a patient in a resource-limited setting with poor or no access to viral load monitoring, or where structural factors and competing priorities adversely impact adherence, reassure that patient with the same certainty as they could an individual who doesn’t have these concerns? -,Strictly speaking, U=U applies to the risk of sexual transmission; can we reliably apply this message in the context of breastfeeding, to a healthcare worker following a sharps injury or to an HIV negative individual who shares a syringe during intravenous drug use? -,Should we offer post-exposure prophylaxis to a patient with a sexually transmitted infection whose sexual partner informs him or her that they have an undetectable viral load? So, while at an individual level, U=U provides powerful motivation for adherence to treatment and retention in care, it is crucial that we continue to strive for answers to the many as yet unanswered questions that still remain.