By the late 1970s it had become clear that the immunosuppressive effects of conventional anti lymphocyte serum (ALS) were mediated by only a small component of the anti lymphocyte antibodies present. This fact meant that attempts to improve the safety, potency and standardisation of conventional ALS by raising xenosera to single, purified lymphocyte antigens were faced with considerable technical and theoretical problems. Coincidentally and very fortunately, it was at this time that the potential of monoclonal antibodies in the field of ALS were becoming obvious. Their advent has dramatically transformed the situation, from a bleak one with few prospects to one where the early promise of ALS is likely to be realised in the clinic within the next few years. This review looks at why it is that monoclonal antibodies have so changed the situation, and then discusses in detail the optimal properties, in terms of specificity and other characteristics, of immunosuppressive monoclonal antibodies, and finally looks at precisely how they should be used in the clinic.