In contrast to other species, cattle possess exceptional antibodies with ultra-long complementarity-determining regions (ulCDRs) that can consist of 40-70 amino acids. The bovine ulCDR is folded into a stalk and a disulfide-rich knob domain. The binding to the antigen is via the 3-6 kDa knob. There exists an immense sequence and structural diversity in the knob that enables binding to different antigens. Here we summarize the current knowledge of the ulCDR structure and provide an overview of the approaches to discover ulCDRs against novel antigens. Furthermore, we outline protein engineering approaches inspired by the natural ulCDRs. Finally, we discuss the enormous potential of using isolated bovine knobs, also named picobodies, as the smallest antigen-binding domains derived from natural antibodies.