After Saint Marys Hospital opened in 1889, physicians and surgeons of the pioneer Mayo family practice made only incidental examinations of their patients' urine, blood and sputum, shifting that work instead to Dr. Christopher Graham. Dr. Graham joined the group in 1894 and took over urinalysis and some simple blood analyses, which then included leukocyte counts.

Because of Dr. Will Mayo's interest, Dr. Graham inaugurated gastric analysis. In late 1898, Dr. Melvin Millet joined Mayo as a resident physician at Saint Marys Hospital. A laboratory was set up for him in the hospital's basement, and patients with stomach symptoms were sent there for test-meal analysis. In addition to this routine, Dr. Millet studied gastric ulcer. Then Dr. Will's desire to improve diagnosis of renal disease drew Dr. Millet into learning cytoscopy. About that time, Dr. Isabella Herb joined the staff, and along with her anesthesia duties in surgery, she worked in pathology.

With the arrival of Dr. Henry Plummer in 1901, laboratory work at Mayo acquired a passionate, articulate advocate. In 1905, Dr. Plummer supported the hiring of Dr. Louis Wilson. Thus, the development of Mayo's modern-day laboratories was initiated.