Some untranslated sequence (UTR)-localized, short tandem repeats (STRs) exhibit evidence of selection pressure, including STR-coupling preferences, STR conservation, interspecies STR-STR replacements, and STR variants implicated in certain diseases. We wished to determine if STR replacements occurred near disease-related genes, including previously unstudied STRs as well as some STRs already implicated in disease. Among nine strong-candidate prostate cancer (CaP)-predisposing genes, three [steroid 5-alpha-reductase 2 (Srd5A-2), macrophage scavenger receptor-1 (MSR-1), and tumor necrosis factor receptor-21 (Tnfr-21)] exhibited striking STR replacements (P<0.001). The glomerular disease-related gene, CD2AP, exhibited an STR replacement flanked by well-conserved sequences, suggesting an STR-focused process. Another glomerular disease-related gene, rabphilin 3A, exhibited at least two STR replacements at the same UTR position comparing Drosophila melanogaster, Mus musculus, and Homo sapiens. Two genes implicated in blood-clotting disorders, von Willebrand factor (vWA) and fibrinogen alpha (FGA), exhibited multiple-intron STR replacements among mammals, extending STR replacement phenomena to introns. Among primates, a tyrosine hydroxylase (THO1) intron STR, previously implicated in both schizophrenia and drug withdrawal delirium, exhibited frequent replacements. Some STR replacements were early events in gene divergence. When STR sequences of closely related species were available, STR replacement was observed to be nearly as rapid as speciation. STR replacements expand the list of STR sequences that may contribute to genetic activity and to disease processes.