Over the past decade, encouraging preclinical and early clinical data concerning the relevance of the insulin receptor/insulin-like growth factor (IGF) receptor family to neoplasia led to ambitious clinical trial programs of more than a dozen drug candidates that target these receptors. These candidates include antireceptor antibodies, antiligand antibodies, receptor-specific tyrosine kinase inhibitors, and agents such as picropodophyllin and metformin that have novel mechanisms of action. Several recently reported phase III clinical trials of anti-IGF-I receptor antibodies have been disappointing and are sufficient to disprove the hypothesis that the antibodies tested have large favorable impacts on unselected patients with cancer. However, many of these trials were designed prior to recent insights concerning pathophysiology and predictive biomarkers. Future studies are required, but it will be important to optimize their design rather than simply repeat the approaches taken to date.