Tonegawa was born at Nagoya in Japan and educated at Kyoto University and the University of California, San Diego. He worked at the Basle Institute for Immunology from 1971 and in 1981 was appointed professor of biology at the Center for Cancer Research and Department of Biology of the Massachusetts Institute of Technology.

Working at Basle in collaboration with Niels Jerne and Nobumichi Hozumi, Tonegawa revealed how the immune system is capable of generating the enormous diversity of antibodies required so that whatever the nature of the invading organism or ‘foreign’ tissue a suitable antibody is available to bind specifically to it. This implies that the immune system's antibody-producing cells – the B-lymphocytes – can potentially manufacture billions of different antibodies; yet, even in humans, these cells carry only about 100,000 genes on their chromosomes.

Working with mouse cells, Tonegawa showed that during the development of the antibody-producing cell, the genes coding for antibody are shuffled at random, so that in the mature cell a cluster of functional genes is formed specific to that cell. Each individual mature cell thus produces its own specific antibody. This potential diversity is amplified by the fact that each antibody molecule comprises four protein chains, all with a highly variable terminal region. Hence the diversity of antibodies is a consequence of the huge numbers of lymphocytes present in the body, each with its own combination of functional antibody-producing genes. In recognition of the significance of his discovery Tonegawa was awarded the 1987 Nobel Prize for physiology or medicine.