The framing of HIV/AIDS as a crisis has facilitated the rollout of large-scale intervention programmes that represent an enormous effort at mainstreaming biomedical rationalities and neoliberal notions of responsibilisation and self-care. Based on a ‘logic of choice’ (Mol 2008) and ‘responsibilised citizenship’ (Robins 2005a), although veiled in a language of rights and partnership, the heavy focus on individual behaviour and a pharmaceutical ‘solution’ to AIDS shifts the burden of responsibility for the success of the heavily funded programmes onto the shoulders of the patients and conceals alternative forms of responsibility. Analysing how HIV-positive people in Tanzania navigate life with HIV and the complex treatment regimens, this paper looks beyond biomedical rationality, which places the preservation of individual biological life at the centre of its logic, and analyses people's constant struggle to negotiate the meaning of ‘responsible behaviour’ in the context of their lived realities. This repositions the notion of responsibility in the realm of the social and reveals the rationality behind apparently irrational practices.