Members of the signal transducers and activators of transcription (STAT) pathway, which were originally identified as key components linking cytokine signals to transcriptional events in cells, have recently been demonstrated to have a major role in cancer. They are cytoplasmic proteins that form functional dimers with each other when activated by tyrosine phosphorylation. Activated STAT proteins translocate to the nucleus to regulate expression of genes by binding to specific elements within gene promoters. Constitutive activation of the STAT family members Stat3 and Stat5, and/or loss of Stat1 signaling, is found in a large group of diverse tumors. Increasing evidence demonstrates that STAT proteins can regulate many pathways important in oncogenesis including cell-cycle progression, apoptosis, tumor angiogenesis, tumor-cell invasion and metastasis, and tumor-cell evasion of the immune system. Based on these findings, a growing effort is underway to target STAT proteins directly and indirectly for cancer therapy. This review will highlight STAT signaling pathways, STAT target genes involved in cancer, evidence for STAT activation in human cancers, and therapeutic strategies to target STAT molecules for anticancer therapy.