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In veterinary clinical practice, conventional pharmacological treatments such as commercial capsules, tablets, or oral liquids may be difficult to administer to feline patients. Noncompliance, which is estimated to account for the majority of treatment failures, may potentially be overcome with alternative, customized treat- ment options such as topically applied, permeation-enhancing (transdermal) unlicensed medications. These medications allow for the percutaneous absorption of drugs into and through the animal's skin, bypassing the first-pass metabolism, potentially allowing for greater bioavailability, and thus decreasing dosage to achieve therapeutic effects. In these case reports, the efficacy of two unlicensed transdermal medications is demonstrated by the successful treatment of three feline patients, refractory to conventional pharmacotherapy. In case 1, the veterinary physician prescribed gabapentin 10 mg/0.1 mL topical Lipoderm, a permeation-enhancing base, to be applied three times a day inside the cat's ear, in order to manage the unconscious fits following a road traffic accident. In cases 2 and 3, two cats were prescribed fluoxetine 40-mg/g topical Lipoderm, to be applied once a day, in order to manage the inappropriate behavior (urination and defecation). Following three months of transdermal treatment, the quality of life of the three cats and their owners increased considerably, as demonstrated by the results of the validated, Health Related Quality of Life questionnaires employed before treatment (retrospectively) and after treatment. Permeation-enhancing (transdermal) medications are a promising dosage form in veterinary pharmacotherapy. The benefits and versatility of these alternative, customized treatment options are worth considering in current therapeutics.