The antigen-binding site of antibodies from vertebrates is formed by combining the variable domains of a heavy chain (VH) and a light chain (VL). However, antibodies from camels and llamas are an important exception to this in that their sera contain, in addition, a unique kind of antibody that is formed by heavy chains only. The antigen-binding site of these antibodies consists of one single domain, referred to as VHH. This article reviews the mutations and structural adaptations that have taken place to reshape a VH of a VH-VL pair into a single-domain VHH with retention of a sufficient variability. The VHH has a potent antigen-binding capacity and provides the advantage of interacting with novel epitopes that are inaccessible to conventional VH-VL pairs.