Cyclophilins (Cyps) are crucial to protein folding because that the ubiquitous proteins affect the cis-trans isomerization of Pro amide bonds. The immunosuppressive natural product cyclosporine A inhibits the enzymatic activity of the cyclophilins. Chemical modification of cyclosporine scaffolds has produced many analogues that inhibit cyclophilins in vitro but have reduced immunosuppressive properties. Three nonimmunosuppressive cyclophilin inhibitors (alisporivir, SCY-635, and NIM811) have demonstrated clinical efficacy for the treatment of hepatitis C infection. Recent publications suggest that cyclophilin inhibitors may have utility for the treatment of diverse viral infections, inflammatory indications, and cancer. In this review, we document the structure-activity relationships of the nonimmunosuppressive cyclosporins in clinical and preclinical development. Aspects of the pharmacokinetic behavior and chemical biology of these drug candidates are also described.