Angiogenesis was postulated to be a critical prognostic factor and therapeutic focus for malignancy more than two decades ago. Recent studies indicate quantitative assessments of microvessel count to be an independent prognostic variable for disease-free and overall survival in a wide variety of tumors, and that angiogenesis may be a feasible target against which to intervene pharmacologically. Several new and old agents have been found to have anti-angiogenic activity and have reached clinical trial. This review will focus on four agents under investigation in the US: carboxyamido-triazole (CAI), thalidomide, TNP-470 and interleukin (IL)-12. CAI, originally identified for its anti-invasive capacity, has been shown to inhibit tumor and endothelial cell proliferation by inhibition of calcium uptake. It is administered orally, is generally well tolerated, and has been shown to induce disease stabilization and occasional reductions in tumor mass. Thalidomide was shown to inhibit growth factor-induced neovessel formation, a process that can also explain its earlier devastating clinical toxicity. It is administered orally, and is currently in phase II clinical trials for prostate cancer, glioblastoma multiforme and breast cancer. TNP-470 is a fumagillin analog that has been shown in in vivo models to be a potent inhibitor of angiogenesis at concentrations that are cytostatic to endothelial cells and tumor cells. Lastly, IL-12 may exert its anti-angiogenic effects through activation of interferon-gamma to up-regulate interferon-inducible protein-10, an anti-angiogenic cytokine. Phase I clinical trials of IL-12 have shown disease stabilization in several tumor types in response to s.c. administration or using genetically engineered IL-12-expressing patient fibroblasts. These promising new agents join the matrix metalloproteinase inhibitors as important new drugs in the anti-cancer armamentarium.