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Resistance to anthracyclines and taxanes remains a major barrier to effective breast cancer treatment, particularly in aggressive subtypes such as triple-negative breast cancer. Although these agents form the backbone of systemic chemotherapy, variability in response limits long-term survival benefits and underscores the urgent need for predictive biomarkers and novel therapeutic strategies. Emerging evidence implicates Rho family small GTPases and their downstream effectors, p21-activated kinases (PAKs), as central regulators of cytoskeletal remodeling, epithelial-mesenchymal transition, and survival signaling. Aberrant activation of the Rho/PAK axis enhances tumor cell adaptability through cross-talk with PI3K/AKT, MAPK, and NF-κB pathways, promoting DNA repair, apoptosis evasion, and multidrug efflux via P-glycoprotein. These mechanisms converge to reduce chemosensitivity, drive recurrence, and worsen patient outcomes. This review synthesizes current evidence linking Rho/PAK signaling with chemotherapy resistance, discusses its potential as a predictive biomarker for patient stratification, and explores therapeutic opportunities to restore chemosensitivity. Integrating molecular insights into clinical strategies may enable more effective, personalized treatment approaches in breast cancer.