Imiquimod (IMQ) ia an immunostimulating drug used for the treatment of neoplastic skin diseases, such as actinic keratosis (AK) and superficial basal cell carcinoma (sBCC), and as adjuvant for vaccination. Imiquimod formulation and skin delivery is highly challenging because of its very low solubility in most pharmaceutical excipients and poor penetration properties. Objectives of the work were: (1) to evaluate IMQ solubility in different solvents and pharmaceutical excipients; (2) to evaluate IMQ skin retention after the application of simple saturated solutions; (3) to evaluate the role of stratum corneum and solvent uptake on IMQ skin retention and (4) to formulate IMQ in microemulsions – prepared using previously investigated components – and compare them with the commercial formulation. The results show that IMQ solubility is not related to the solubility parameter of the solvents considered. The highest solubility was found with oleic acid (74 mg/ml); in the case of PEGs, the solubility increased linearly with MW (PEG 200: 1.9 mg/ml; PEG 400 7.3 mg/ml, PEG 600 12.8 mg/ml). Imiquimod skin retention from saturated solutions (Tween 80, oleic acid, propylene glycol, PEG 200, PEG 400, PEG 600, Transcutol, 2-pyrrolidone, DMSO) resulted relatively similar, being 1.6 μg/cm2 in case of oleic acid (solubility 74 mg/ml) and 0.18 μg/cm2 in case of propylene glycol (solubility 0.60 mg/ml). Permeation experiments on stripped skin (no stratum corneum) and isolated dermis as well as uptake experiments on isolated stratum corneum sheets demonstrated that IMQ accumulation is related to skin solvent uptake. Finally, microemulsions (MEs) prepared with the above-studied components demonstrated a very good performance. In particular, a ME composed of 10% oleic acid, 35% Transcutol, 35% Tween 80 and 20% water is able to accumulate the same amount of drug as the commercial formulation but with far more efficiency, since its concentration was 12 times lower.