The Holy Grail of cardiovascular pharmacology has been the search for an effective therapy targeting restenosis after angioplasty and/or intra-arterial stenting. The failure of promising therapeutics in clinical trials underscores the complexity and redundancy of the signaling cascades regulating mitogenesis and fibrogenesis. Novel therapeutic modalities have potential to target dysfunctional signaling elements directly in vascular smooth muscle cells. Significant progress in the treatment against restenosis will require the exploitation and cross-fertilization of developments in the fields of pharmacology, bioengineering, genetics, and molecular biology. Collaboration among researchers in these fields will be essential.