BACKGROUND Ubiquitously expressed in the human body, glycoprotein 130 (gp130) is a shared subunit of receptor complexes for at least nine cytokines (IL-6, OSM, LIF, IL-11, CNTF, CLC, IL-27, CT-1, and NP) that mediate highly diverse biological processes. Dysregulation of gp130 expression, activation, or associated signaling pathways are implicated in a variety of human diseases, including cancer. Accumulating evidence indicates that the gp130-mediated signaling networks play important roles in the progression of multiple types of cancer. METHODS This review discusses the structural basis of gp130 in signal transduction activity and its role in physiological and pathological conditions, particularly cancer. We analyzed the currently available databases to illustrate the expression of gp130, its coexpression with other molecules involved in the gp130 signaling pathways, and the role of gp130 in cancer progression. Finally, we highlight strategies for blocking gp130 signaling and the currently available antagonists. CONCLUSIONS As gp130 signaling mediates cancer progression, inhibition of gp130 activity offers a potential and promising approach to cancer therapy. Compared to antibodies blocking individual cytokines, gp130-targeted small-molecule inhibitors present multiple advantages. To achieve successful clinical outcomes for gp130-targeted cancer therapy, dosage determination, duration of therapy, and patient selection are some of the critical factors to be considered.