The hallmark of the antibody response to antigenic challenge is its remarkable specificity. In this Croonian Lecture in 1905, Ehrlich recognized it as a biological puzzle, but considered it inconceivable that animals could produce substances capable of specific recognition of toxins that the species had never encountered before. It took the largest part of the following 70 years to begin to understand the chemical base of the biological puzzle. Even more recently, the genetic base of the underlying events has been clarified. Unique genetic rearrangements of the DNA initiate the biological diversity of somatic cells; this provides an initial source of antigen recognition. The remarkable specificity is the result of an antigen-driven Darwinian selection of proliferating clones, operating on further diversity that is generated by a high rate of point mutations in specific genes. Although the complexity of the biological events underlying the process remain largely unknown, the knowledge gained so far provides insights into alternative approaches to the production of new antibodies.