More than 1 000 000 people are diagnosed with skin cancer each year in the United States, and more than 10 000 people die from the disease. Methods such as visual inspection and dermoscopy are available for early detection of skin cancers, but improvement in accuracy is needed. This paper investigates the use of microwave reflectometry as a potential diagnostic tool for detection of skin cancers. Open-ended coaxial probes were used to measure microwave properties of skin. The influences of measurement parameters such as probe application pressure, power level, and variation in reflection properties of skin with location and hydration were investigated. Using an available electromagnetic formulation, providing for the reflection properties of a layered dielectric structure irradiated by a coaxial probe, measurement and simulation results were compared. The results of the measurements and simulations for normal and moistened skin show that the water content of normal skin and benign and malignant lesions may cause significant differences among their reflection properties and subsequently render a malignant lesion detectable. The results of microwave measurements performed on human subjects are also presented, which show the potential of this technique to distinguish between cancerous and benign lesions.