Sexually transmitted infection (STI) rates are increasing for most nationally notifiable disease categories in the United States. The 2021 Centers for Disease Control and Prevention STI guidelines provide several updated, evidence-based testing and treatment recommendations. The recommended treatment for gonorrhea is ceftriaxone monotherapy given intramuscularly, with dosing based on the patient's body weight. For chlamydia, doxycycline is the preferred treatment. A test-of-cure is recommended for all cases of pharyngeal gonorrhea and for rectal chlamydia if treated with azithromycin. Vaginal trichomoniasis should be treated with a seven-day regimen of metronidazole. Treatment of pelvic inflammatory disease routinely includes metronidazole with doxycycline and an increased dosage of ceftriaxone. Syphilis of less than one year's duration should be treated with a single dose of intramuscular penicillin G benzathine, 2.4 million units. Syphilis of more than one year's or unknown duration should be treated with three consecutive weekly doses of intramuscular penicillin G benzathine, 2.4 million units each. A thorough evaluation for otic, ophthalmic, and neurologic symptoms is essential for anyone with syphilis because these complications can occur at any stage and require 10 to 14 days of treatment with intravenous aqueous crystalline penicillin G. Family physicians can reduce STI rates by taking a thorough sexual history, especially in teens and young adults, ordering screening tests and treatment based on the updated Centers for Disease Control and Prevention STI guidelines, and collaborating with public health departments for disease reporting and partner services.