The techniques now exist to deliver drug infusions reliably through the hepatic artery to infuse the entire liver and tumor within the liver. Drug selection for use in these systems should be rational and include agents with short half-lives (high total body clearance) and some evidence of activity against the tumor type in question. Hepatic extraction and metabolism of the drug will in turn decrease systemic exposure or allow more drug to be given per set amount of systemic exposure. The dose-limiting toxicity of appropriate drug programs may well be regional and not systemic. Further pharmacokinetic studies and controlled clinical trials are needed to evaluate existing regimens and to design new regimens. Future advances are likely to involve the combination of effective drugs and the use of therapeutic microspheres to improve selectivity based on tumor microcirculation.