A variety of pharmacologic options are available to clinicians who want to provide effective and safe topical local anesthesia to children undergoing venous access procedures. These options can be distinguished on the basis of how they deliver active drug through the impermeable outer layer of skin, the stratum corneum, to pain receptors located in the dermis and epidermis. Three general methodologies are typically used to bypass the stratum corneum: direct injection of local anesthetics, usually via a small-gauge hypodermic syringe; passive diffusion from topical creams or gels; and active needle-free drug strategies that enhance the rate of drug passage into the dermis and epidermis. Examples of the latter mechanisms include heat-enhanced diffusion, iontophoresis, sonophoresis, laser-assisted transdermal passage, and pressurized gas delivery of powdered drug particles. Pharmacologic options in this setting can also be distinguished on the basis of the time to onset of full anesthetic effect. Several available agents induce significant local anesthesia within 1 to 3 minutes of administration, or faster, allowing easy integration into the skin preparation and subsequent venous access procedure. In combination with nonpharmacologic approaches, these agents can be used to dramatically lessen this significant source of pediatric pain.