Focusing on the rights of children who are deprived of their family environment and remain in child-headed households in the context of the HIV epidemic in Africa cannot be more relevant at present as the continent faces a significant increase in the number of children who are left to fend for themselves due to the impact of the epidemic. The impact of the epidemic is so severe that it is likened to an armed conflict. In sub-Saharan Africa, an estimated 22.4 million people are living with HIV, and in 2008 alone, 2 million people died of AIDS-related illnesses. Such massive loss of human lives is itself a tragedy. However, the repercussions of the epidemic suffered by children may be less visible, yet are just as far-reaching, and in all likelihood longer lasting in their effects. Initially, it appeared that children were only marginally affected by the epidemic. Unfortunately, it is now clear that children are at the heart of the epidemic. In sub-Saharan Africa, an estimated 14 million children lost their parents to AIDS-related illnesses and an unimaginable number of children consequently find themselves in deepened poverty. Traditionally, children who are deprived of their family environment in Africa have been cared for by extended families. However, the HIV epidemic has dramatically affected the demography of many African societies. As the epidemic continues to deplete resources of the affected families and communities, extended families and communities find it more and more difficult to provide adequate care to the increasing number of children who are deprived of parental care. As a result, more and more children are taking care of themselves in child-headed households. The foremost responsibility of states with regards to children who are deprived of parental care is to support families and communities so that they are able to provide adequate care to children in need of care, thereby preventing children from being deprived of their family environment. While strengthening families and communities, as required by articles 20 of the Convention of the Rights of the Child and 25 of the African Charter on the Rights and Welfare of the Child, as well as other international guidelines such as the 2009 UN Guidelines for the Alternative Care of Children, states also have the responsibility to provide ‘special protection and assistance’ to children who are already deprived of their family environment and are living in child-headed households. The important question is how to interpret the right to alternative care, and special protection and assistance, with respect to children in child-headed households. The study examines the international standards and norms regarding children who are deprived of their family environment including children in child-headed households and explores the ways those children are supported and protected in South Africa, against the background of related developments in a number of different African countries, including Namibia, Southern Sudan and Uganda. In 2002, the South African Law Reform Commission made the important recommendation that child-headed households should be legally recognised. The Children’s Amendment Act (No 41 of 2007), which amended the comprehensive Children’s Act (No 38 of 2005) gave effect to this recommendation by legally recognising child-headed households under prescribed conditions. It is a bold step to strengthen the protection and assistance given to children in child-headed households. However, child-headed households should not be legally recognised unless all the necessary protection and assistance measures are effectively put in place. In order to design and implement the measures of protection and assistance to children in child-headed households, a holistic children’s rights-based approach should be a guiding light. A rights-based approach, which articulates justiciable rights, establishes a link between the entitlement of children as rights-holders and legal obligations of states as duty-bearers. States have the primary responsibility to provide appropriate protection and assistance to children who are deprived of their family environment. This is a legal obligation of states, not a charitable action. A rights-based approach is further important in that it ensures that both the process of mitigation strategies and the outcome of such efforts are firmly based on human rights standards. The study argues that legal recognition should be given to child-headed household only after a careful evaluation based on the international standards with regard to children deprived of their family environment. It further argues that measures of ‘special protection and assistance’ should be devised and implemented using a rights-based approach respecting, among others, children’s rights to non-discrimination, to participation and to have their best interests given a priority.