This editorial review covers current trends in the epidemiology of HIV among people who inject drugs (PWID) in the United States, including four recent HIV outbreaks. We discuss gaps in the prevention and treatment cascades for HIV and medications for opioid disorder and propose lessons learned to prevent future HIV outbreaks. Over the last decade, North America has been in the throes of a major opioid epidemic, due in part to over-prescribing of prescription opiates, followed by increasing availability of cheap heroin, synthetic opioids (e.g. fentanyl), and stimulants (e.g. methamphetamine). Historically, HIV infection among PWID in the US had predominantly affected communities who were older, urban and Black. More recently, the majority of these infections are among younger, rural or suburban and Caucasian PWID. All four HIV outbreaks were characterized by a high proportion of women who inject drugs and underlying socioeconomic drivers such as homelessness and poverty. We contend that the US response to the HIV epidemic among PWID has been fractured. A crucial lesson is that when evidence-based responses to HIV prevention are undermined or abandoned because of moral objections, untold humanitarian and financial costs on public health will ensue. Restructuring a path forward requires that evidence-based interventions be integrated and brought to scale while simultaneously addressing underlying structural drivers of HIV and related syndemics. Failing to do so will mean that HIV outbreaks among PWID and the communities they live in will continue to occur in a tragic and relentless cycle.