[1] He examined various problems in agricultural chemistry, including the composition of soils, the value of marls and fossil bones, and the growing of cotton.

Smith returned to the United States in 1850, and perfected the inverted microscope, an invention which he had begun working on while abroad.

[8][9] He was apparently offered a professorship at the University of New Orleans, but wrote in December, 1850, that it "at present exists but in name."

He described himself as a "peripatetic philosopher" and lamented his lack of a settled laboratory, writing "All my scientific labors have as yet been carried on in the Gipsey style.

[1] In the autumn of 1852[1] he took up a professorship in the chair of chemistry at the University of Virginia, replacing Robert Empie Rogers, who moved to Philadelphia.

[1] As a result of his father-in-law's appointment as Secretary of the Treasury in 1853, the couple moved to Washington, D.C. where Sarah served as a hostess for her father.

Smith was able to do some work at the Smithsonian Institution and gave lectures for the US Department of Agriculture, but had little opportunity for research.

His interest in meteorites predated his retirement from Louisville; his earliest paper on the subject was read before the American Association for the Advancement of Science in April, 1854.