Spencer de Grey studied architecture at Cambridge University under Sir Leslie Martin. On leaving Cambridge in 1969, he worked for the London Borough of Merton on one of the first middle schools in the country.

He joined Foster Associates in 1973, continuing his work in education on the Palmerston Special School in Liverpool. He then worked on the Hammersmith Centre before setting up Foster Associates' Hong Kong office in 1979 to build the Hong Kong and Shanghai Bank. In 1981 he returned to London, becoming the director in charge of Stansted Airport, which he saw through to completion in 1991. During this period, he also worked on the BBC Radio Centre and was responsible for the Sackler Galleries at the Royal Academy of Arts in London.

Since his partnership in 1991 he has overseen a wide range of projects, including the Commerzbank Headquarters in Frankfurt, the Law Faculty at Cambridge University, the Great Court at the British Museum, the Great Glasshouse at the National Botanic Garden of Wales, the redevelopment of Dresden Station, The Sage (Music Centre) Gateshead, HM Treasury in Whitehall, seven new City Academy schools in the UK and Walbrook Square, a major redevelopment in the City of London.

He is also responsible for a number of projects in the USA including the master plan and first phase of the Boston Museum of Fine Arts, the new Opera House in Dallas, Avery Fisher Hall at New York's Lincoln Center and the competition-winning scheme for the courtyard shared by the National Portrait Gallery and the Smithsonian American Art Museum, both part of the Smithsonian Institution, Washington DC.

He lectures widely, is an architectural advisor for the Royal Botanical Gardens in Kew, Chairman of the Building Centre Trust, Chairman of the Cambridge University School of Architecture Advisory Board and a member of the Mayor’s Design for London Advisory Board. He was made a CBE in the Queen's Birthday Honours of 1997 and more recently, a Fellow of the Royal Society of Arts. Now Senior Executive, he has assumed a broader role in the office and shares overall design responsibility for all projects as joint Head of Design.