Although many DNA aberrations in melanoma have been well characterized, including focal amplification and deletions of oncogenes and tumor suppressors, broad regions of chromosomal gain and loss are less well understood. One possibility is that these broad events are a consequence of collateral damage from targeting single loci. Another possibility is that the loss of large regions permits simultaneous inactivation of multiple tumor suppressors, by broadly decreasing the resident gene dosage and expression. Here, we test this hypothesis in a targeted fashion using RNA interference to suppress multiple candidates resident in broad regions of loss. We find that loss of chromosome regions 6q, 10, and 11q21-ter are correlated with broadly decreased expression of most resident genes, and that multiple resident genes impacted by broad regional loss of chromosome 10 are bona fide tumor suppressors capable of affecting tumor growth and/or invasion. We also provide functional support for Ablim1 as a novel tumor suppressor. Our results support the hypothesis that multiple cancer genes are targeted by regional chromosome copy number aberrations.