[9] The first ever AIDS cases were reported on 5 June 1981 in the United States Center for Disease Control and Prevention (CDC)'s weekly epidemiological digest Morbidity and Mortality Weekly,[7][11] which described rare pneumonia in five patients and "the possibility of a cellular-immune dysfunction related to a common exposure that predisposes individuals to opportunistic infections such as pneumocystosis and candidiasis".

[12][13] As Lindsay Knight summarises the understanding and outlook of the early 1980s in her report, UNAIDS: The first ten years, 1996–2006:[7]: 7  "No one could have imagined that a few cases of rare diseases damaging the immune system would herald a pandemic that has killed more than all those who died in battle during the whole of the twentieth century."

The report further argues that the CDC's approach, along with partnerships with the US Food and Drug Administration, and the National Institutes of Health, are the reason that initial recommendations for diagnosis, treatment, and containment were developed, issued and disseminated so quickly (within 1–2 years of first reported case), The report states that the CDC's "excellent surveillance, rapid identification, innovative science, committed persons", among other factors help to "illustrate the power of epidemiologic investigation in understanding and preventing new diseases, even in the absence of an identified cause" and that the "CDC's reputation and staff accomplishments led to the formation of the Global AIDS program.

[7] One book which examines the global response, and describes both the positive and negative aspects states that during the first fifteen years of the HIV/AIDS crisis, "most of the world's leaders, in all sectors of society, displayed a staggering indifference to the growing challenge of this new epidemic."

It explains that a combination of factors – (1) biases and stereotyped views that those ill were only from stigmatized communities such as sex workers, men who have sex with men, drug users, migrants, among others, as well as (2) political issues such as countries not wanting to admit there was a crisis and taking steps to block journalists and media reports on the breakout, (3) politicians falsely believing that the disease was limited to lower income countries with less developed medical and healthcare systems, and some politicians fear of associating their own country with sex and death – all led to a slow response, and low levels of funding for research, treatment, and support at a time when greater actions could have been taken.

[7] Sidibé offered his resignation from his post as head of UNAIDS following an expert report on sexual harassment in the agency that criticized his "defective leadership".

[14] In response to heightened scrutiny and reports of his gross mismanagement, however, Sidibe informed the agency's board on 13 December 2018 that he would leave his post in June 2019.

[15] A panel of independent experts released a report on 13 December 2018 saying Sidibe was overseeing a "patriarchal" workplace and promoting a "cult of personality" centred on him as the all-powerful chief.

In particular, it calls for complementation of government efforts by the full and active participation of civil society, the business community and the private sector through: UNAIDS works to promote partnerships among and between this diverse and broad range of non-state entities.

With the momentum generated by the UN Special Session on HIV/AIDS, the main challenges are to: UNAIDS has collaborated with the Roman Catholic Church, especially Caritas Internationalis, in the fight against AIDS, something which materialized in a December 2005 message by Pope Benedict XVI.

[21] In engaging non-state entities in an expanded response to the epidemic, the UNAIDS Secretariat: As the main advocate for global action on HIV/AIDS, UNAIDS leads, strengthens and supports an expanded response aimed at preventing the transmission of HIV, providing care and support, reducing the vulnerability of individuals and communities to HIV/AIDS, and alleviating the impact of the epidemic.

To fulfil this mandate, UNAIDS is supported by voluntary contributions from governments, foundations, corporations, private groups (for example, students, universities, sporting clubs, etc.)

[24] UNAIDS has several Goodwill Ambassadors who help strengthen awareness of the organisation's work, including:[25] Quarraisha Abdool Karim, Myung-Bo Hong, Toumani Diabaté, Crown Princess Mette-Marit of Norway, Princess Stephanie of Monaco, Naomi Watts, Aishwarya Rai Bachchan, Vera Brezhneva, Victoria Beckham,[26] Chantal Biya[27] and Pia Wurtzbach.