The brain is a target of HIV-1 and serves as an important viral reservoir. Astrocytes, the most abundant glial cell in the human brain, are involved in brain plasticity and neuroprotection. Several studies have reported HIV-1 infection of astrocytes in cell cultures and infected brain tissues. The prevailing concept is that HIV-1 infection of astrocytes leads to latent infection. Here, we provide our perspective on endocytosis-mediated HIV-1 entry and its fate in astrocytes. Natural entry of HIV-1 into astrocytes occurs via endocytosis. However, endocytosis of HIV-1 in astrocytes is a natural death trap where the majority of virus particles are degraded in endosomes and a few which escape intact lead to successful infection. Thus, regardless of artificial fine-tuning (treatment with cytokines or proinflammatory products) done to astrocytes, HIV-1 does not infect them efficiently unless the viral entry route or the endosomal enzymatic machinery has been manipulated.