Established by Congress to combat a wide range of animal diseases—from infectious disease of swine to bovine pneumonia, Texas cattle fever to glanders—Smith worked under Daniel E. Salmon, a veterinarian and Chief of the BAI.

After two years of work studying the efficacy of bacterial vaccination in pigs, Smith erroneously believed he had found the causative agent of hog cholera.

[7] Smith turned his attention to Texas fever, a debilitating cattle disease; this work is detailed in a chapter in Microbe Hunters, by Paul de Kruif.

In 1887, Smith began research on water sanitation in his spare time, investigating the level of fecal coliform contamination in the nearby Potomac River.

[8] While Smith's work at the BAI had been highly productive, he found the rigid federal government bureaucracy stiffing and complained about the lack of leadership from his supervisor.

[9] Smith's best-known contribution was the notion, long since disproved, that there would be a “delicate equilibrium” between hosts and pathogens such that they would develop a "mutually benign relationship" over time.