Resistance to conventional cancer therapies such as chemotherapy, radiotherapy, immunotherapy, and targeted therapy remains a major obstacle in effective treatment. Tumor cells employ diverse mechanisms to evade therapeutic effects, including drug efflux via ATP-binding cassette transporters, alterations in drug targets, increased DNA damage repair, inhibition of apoptosis, and activation of pro-survival signaling pathways. Additionally, tumor heterogeneity, epithelial to mesenchymal transition (EMT), cancer stem cells, and interactions within the tumor microenvironment contribute to both intrinsic and acquired resistance. These mechanisms not only reduce treatment efficacy but also promote relapse, metastasis, and poor patient outcomes. Understanding the molecular, and cellular basis of resistance is critical for designing novel therapeutic interventions, and combinatorial strategies. This chapter explains the pathways underlying resistance to conventional therapies, highlights the role of tumor plasticity, and discusses emerging approaches aimed at overcoming resistance to improve long-term cancer management.