The first descriptions of the trisomy 21 phenotype were by Jean-Etienne-Dominique Esquirol (1838), Edouard Séguin (1846) and later by John L. H. Down in 1862. It took more than a century to discover the extra-chromosomal origin of the syndrome commonly called "Down's syndrome" and which, we suggest, should be referred to as "Trisomy 21". In this review we are presenting the landmarks, from the pioneering description of the syndrome in 1838 to Jérôme Lejeune's discovery of the first genetic substrate for mental retardation. The sequencing of HSA21 was a new starting point that generated transcriptome studies, and we have noted that studies of gene over-expression have provided the impetus for discovering the HSA21 genes associated with trisomy 21 cognitive impairment.