The newly discovered external tail loop within the C-terminal tail of the gp41 transmembrane subunit of the HIV-1 envelope protein comprises approximately 40 residues, and within this are 18-residues ((734)PDRPEGIEEEGGERDRDR(751)) that include three antibody-reactive regions. The antigenicity is complex, and changes according to the biological context of the gp41. It is thus of interest both to the HIV specialist and protein immunologists. The antibody-reactive region, centred on the sequence ERDRD, encompasses three distinct epitopes which are expressed in different combinations on infected cells, wt virions, prefusion virion-cell complexes, and a neutralising antibody escape mutant virion. In addition ERDRD-specific antibodies have one or more antiviral activities, and variously neutralise the infectivity of free virions, neutralise virions already attached to the target cell, reduce the production of infectious progeny, and inhibit the ability of infected cells to fuse with non-infected cells. Antibodies to PDRPEG and IEEE have no apparent antiviral activity even though the footprints of the IEEE- and ERDRD-specific antibodies overlap. This review marshals the available experimental data with the aim of understanding the significance of the gp41 tail loop to the HIV-1 life cycle, and its relevance to potential anti-viral measures. There are lessons here, too, that are relevant to the comprehension of the antigenicity of short protein segments in general.