The effect of various electronic and formulation variables on the in vitro permeation profiles and rate of hydromorphone across freshly-excised full-thickness hairless rat skin were investigated. The stability of the hydromorphone hydrochloride solution to the skin enzymes was also determined. Furthermore, the effects of current strength and drug concentration on the pharmacokinetics and pharmacodynamics of hydromorphone were evaluated in vivo in hairless rats. Current was supplied by Phoresor IITM and the Trans Q1 GS patches were used in the in vivo studies. Results showed that by manipulating the electronic and formulation variables the transdermal iontophoretic delivery of hydromorphone hydrochloride can be controlled, and the possibility of obtaining therapeutically effective hydromorphone concentrations for the management of cancer-related pain is feasible by transdermal iontophoresis.