In 1980, Mak returned to Wisconsin to learn new techniques in the lab of Howard Martin Temin, who won the Nobel Prize in Physiology or Medicine in 1975 for his discovery of the enzyme reverse transcriptase. Temin would be one of his mentors that shaped his way of thinking, encouraging him to delve into diverse disciplines. During the early 1980s in Toronto, with his newly setup group, Mak was working on virology. Mak employed a technique called molecular subtraction, used by virologists, to attempt to identify the T-cell receptor, which was so elusive at the time it was referred to as the "Holy Grail of Immunology". In 1984, Mak discovered the T-cell receptor, with Mark M. Davis identifying the receptor in mouse. This work on the cloning of T-cell receptor genes, , has been cited nearly 1200 times. In spite of offers from prestigious institutions around the world, Mak remained committed to Canada’s scientific community.