Chemotherapy-resistant tumors present a significant challenge in oncology, often leading to treatment failures owing to mechanisms such as genetic mutations, drug efflux, altered metabolism, and adaptations within the tumor microenvironment. These factors limit the effectiveness of treatment and contribute to tumor resistance. This review highlights the role of alternative therapies aimed at overcoming resistance mechanisms. Several alternative strategies with high efficacy rate against tumor resistance are being explored, including targeted therapies (58-64%), immunotherapy (80%), hormone therapy (22-61%), and emerging approaches such as herbal therapies (90%), probiotics (34-90%), metabolic therapies (>
50%), epigenetic therapies (51-89%), microbiome-based therapies (50%), gene therapy (67-80%), photodynamic therapy/hypothermia (86-99%), and nanotechnology (50-67%). Integrating these alternative strategies with conventional treatments has the potent-al to augment the therapeutic efficacy and patient outcomes. Despite this progress, limitations in cancer therapeutics include the lack of predictive biomarkers, resistance mechanisms, and tumor heterogeneity, all of which contribute to treatment failure and relapse. To address these limitations, advancements in molecular diagnostics, as well as early detection through liquid biopsies, and the use of biomarkers to monitor resistance and guide treatment are crucial. Additionally, expanding clinical trials is essential to validate new therapies and improve patient outcomes.