There is new hope that we can significantly reduce HIV rates. The United Nations AIDS organization, UNAIDS, has challenged all countries to strive for aggressive targets that could significantly bend the curve on HIV infections and deaths: 90% of people living with HIV diagnosed; 90% of people diagnosed on treatment; and 90% of people on treatment virally suppressed. This new optimism is largely driven by strong research findings that early and ongoing HIV treatment improves individual health outcomes and reduces people's viral load, making them less infectious. However, the risk of HIV infection is far from evenly distributed among populations most at risk. Those most at risk will find it hardest to reach these targets as they are caught in a syndemic (synergistic epidemic) of intertwining health and social issues. Our research, and that of others, shows that those who are in a syndemic of co-occurring mental health, addiction and social issues (e.g. homelessness, food insecurity) are significantly more likely to fall out of care, less likely to adhere to treatment and less likely to achieve/maintain an undetectable viral load. Intervention studies have found that a combination approach to HIV prevention and treatment that goes beyond primary care and mental health tools to include social and structural interventions has a protective effect, and can reduce risk and improve adherence. People living with and at risk of HIV need better access to social and mental health services as well as clinical treatment services that will help them achieve and maintain optimal health and well-being. We strongly encourage those in the HIV sector across the country to identify a common vision, with clear goals and targets. With concerted and targeted efforts, a focus on program and implementation science, and a willingness to see and treat HIV as a social as well as a biomedical problem-the fourth decade of HIV in Canada could well be the last.