After his PhD, smith did postdoctoral research from March 1969 to August 1971 in the Department of Biophysics and Genetics, University of Colorado Medical School, Boulder. His research is centered on the application of various computer science and mathematical methods for the discovery of the syntactic and semantic patterns in nucleic acid and amino acid sequences. In recent years this has focus on molecular evolution of protein families. such as the WD-repeat beta propellers, translation associated GTPase, and the ribosomal proteins. He is known for the creation of the Smith-Waterman algorithm. Smith has held the following appointments:
1965–1966: Instructor, US Air Force Lowery, Denver, CO
M. Mariotti, T. F. Smith, P. H. Sudmant and G. Goldberger, “Pseudogenization of testis-specific Lfg5 predates human/Neanderthal divergence”, Journal of Human Genetics 59, 288–291
Hyman Hartman and Temple F. Smith “The Evolution of the Ribosome and the Genetic Code”, Life, 4, 227–249
Hartman, H and T. F. Smith, “GTPases and the origin of the ribosome”, Biology Direct, 5:36-39,
Hartman, Hyman and Smith, Temple F. “The evolution of the cilium and the eukaryotic cell” Cell Motility and the Cytoskeleton.66: 215-219.
Hu, Lan, Smith, Temple F. and Goldberger, Gabriel. “LFG: a candidate apoptosis regulatory gene family” Apoptosis. 14: 1255-1265.
Smith, Temple F., Lee, Jung C., Gutell, Robin R. and Hartman, Hyman. “The Origin and Evolution of the Ribosome” Biology Direct 3: 16, 1–13
Smith, Temple F. “Chapter 2: Diversity of WD-Repeat Proteins” The Coronin Family of Proteins, 20–30
Bhutkar, Arjun V., Gelbart, William M. and Smith, Temple F.. Inferring genome-scale rearrangement phylogeny and ancestral gene order: A Drosophila case study. Genome Biology 8, R236
Bhutkar, Arjun, Russo, Susan M., Smith, Temple F. and Gelbart, William M. “Genome-Scale Analysis of Positionally Relocated Genes” Genome Research 17: 1880-1887
Hartman, Hyman, Favaretto, Paola and Smith, Temple F. “The Archaeal Origins of the Eukaryotic Translational System” Archaea 2: 1-9
Bienkowska, Jadwiga, Hartman, Hyman and Smith, Temple F.. A search method for homologs of small proteins, Ubiquitin-like proteins in prokaryotic cells? Protein Engineering 16, 897–904.
Venkatesan, Kavitha, McManus, Heather R., Mello, Craig C., Smith, Temple F. and Hansen, Ulla.. Functional conservation between members of an ancient duplicated transcription factor family, LSF/Grainyhead. Nucleic Acids Research 31, 4304–4316.
Zhang YX1, Fox JG, Ho Y, Zhang L, Stills HF Jr, Smith TF. Comparison of the major outer-membrane protein gene of mouse pneumonitis and hamster SFPD strains of Chlamydia trachomatis with other Chlamydia strains. Mol Biol Evol. 1993 Nov;10:1327–42.