In this review of the current challenges in the fight against HIV, we describe the state of the HIV epidemic and the framework put in place using the 90-90-90 objectives to try and curb the epidemic worldwide. There are numerous effective and evidence-based prevention measures against the spread of HIV, but the biggest challenges lie in the lack of political commitment, reluctance to address issues of sexuality and reproduction, and criminalization of key populations that are at the highest risk of HIV. Access to HIV treatment and continued care without stigmatization should be as easy and cheap as possible for those who are tested and diagnosed with HIV to achieve the best results worldwide. Regarding the treatment of HIV, the last decades have been very successful in dramatically improving the quality of life of people living with HIV, reducing the transmission rate and decreasing HIV-associated morbidity and mortality. It could even be argued that the next milestone will be a strategy that allows individuals to stop combination antiretroviral therapy safely before a cure is discovered. Despite great progress, people with HIV have shorter life expectancy than those without the virus, and the underlying causes are probably multifactorial, including premature aging, drug toxicities, and comorbidities. Even if challenges remain, hope should too, with the ultimate goal to end the HIV epidemic.