Smith was educated at Latymer Upper School and graduated from the University of Cambridge with a Bachelor of Arts degree in Natural Sciences in 1976. He was awarded a PhD in 1979 by University College London (UCL) for research supervised by Lewis Wolpert at Middlesex Hospital Medical School.
Smith completed postdoctoral research appointments at Harvard Medical School from 1979 to 1981 and the Imperial Cancer Research Fund (now Cancer Research UK) from 1981 to 1984. In 1984 he joined the staff of the National Institute for Medical Research (NIMR), becoming head of the Division of Developmental Biology in 1991 and head of the Genes and Cellular Control Group in 1996. He moved to become director of the Gurdon Institute in 2001, returning to NIMR in 2009 to become its director. In 2014 he became Deputy CEO of the Medical Research Council. When NIMR joined the CRUK London Research Institute as part of the Francis Crick Institute he became director of research at the Crick. He took up his present roles in December 2016.
Smith’s research has focused on how cells of the very early vertebrate embryo form the specialised tissues of muscle, skin, blood and bone. His discovery of a mesoderm-inducing factor secreted by a cell line and establishing its identity as activin transformed the study of induction in the early embryo. He also showed that activin specifies different cell types at different thresholds and that characteristic genes like Brachyury are turned on at specific concentrations. In other work he shed light on the molecular basis of gastrulation, and especially the role of non-canonical Wnt signalling. His earlier work demonstrated threshold responses in chick limb development and also showed that the mitogenic response to growth factors can be active when attached to the extracellular matrix.