Triamcinolone acetonide is a glucocorticosteroid used in standard clinical practice for its anti-inflammatory properties. Although it can be given via different routes of administration, the intramuscular route is unique compared with other corticosteroids-its effects remain potent over a longer period of time. We summarize the existing literature on the pharmacokinetic and pharmacodynamic mechanisms of intramuscular triamcinolone acetonide (Kenalog(& REG;)). The fascinating nature of the purported efficacy of triamcinolone acetonide may be attributed to differing binding mechanisms, low solubility in blood, a low renal clearance rate, and various metabolites and other yet defined effects on skin. The enigma of the purported efficacy of triamcinolone acetonide may lie in the fact that it has a unique nature of having a long-term effect on dermatologic disease using a seemingly low dose compared with other routes of administration and other corticosteroids. Possible reasons for this may be binding differences at the intramuscular site, low solubility due to acetonide esters, a slow rate of absorption from the injected site, and a low renal clearance rate. There is still much to be learned about its mechanism of action, which may be of clinical and therapeutic significance.