Moving to Johns Hopkins University in 1959, he undertook cytogenetic research on the causes of Turner Syndrome and true hermaphroditism, as well as establishing the first human chromosome diagnostic laboratory in the USA.
Returning to Glasgow, he set up a Regional Genetics Service for the West of Scotland, the population providing the opportunity for continuing clinical genetics research and the development of prenatal diagnosis and screening for Down syndrome and spina bifida.
His work on mapping the Y-linked sex determinant in XX males leading eventually to the isolation of the mammalian sex determining gene 25 years later. Work on translocations in pachytene, gene mapping through chromosome deletion and by in situ hybridisation also proved to be first descriptions in the human genetics literature.
As well as participating in all eleven Human Gene Mapping workshops from 1973-1991, he continued to publish on a range of topics relating to human meiosis, clinical genetics, prenatal diagnosis, and human chromosome mapping.
Ferguson-Smith declined to administer the tests for competitors at the 1970 Edinburgh Commonwealth Games, arguing that the method of testing (the sex chromatin or buccal smear test) would be more likely unfairly to exclude women athletes than detect cheats and called for an end to genetics-based gender verification.
In 1998 he was a member of the Committee of the Inquiry into the emergence and identification of Bovine Spongiform Encephalopathy (BSE) and variant Creutzfeldt-Jakob Disease (vCJD).