Since the beginning of the HIV epidemic, people living with HIV have faced numerous psychological and behavioral challenges. With the advent of antiretroviral therapy (ART) there have been dramatic shifts in some of these key challenges and new ones have come to the forefront. This paper highlights several critical psychological and behavioral aspects of HIV disease, a few of which require focused attention, including mental health, stigma and disclosure, adherence, and sexual behavior. Although the focus is primarily on adults living with HIV, we also comment on some of the additional challenges for children and young people. Our critical examination in these areas draws upon the lessons learned in contexts in which ART has been available for a decade, and we explore what is currently happening in settings with more recent treatment access. In the end we offer our insights into what we may expect in the future, and provide recommendations for ongoing prevention and care initiatives with adults, children, and young people affected by this disease.