Cancer is a fatal disease with increasing morbidities and mortalities worldwide. Considering the millions of deaths due to cancer, effective treatment interventions are urgently needed to halt the devastating mortality rates and disease burden. Current methods of therapy for cancer, such as phototherapy, radiotherapy, surgery, and chemotherapy, are limited due to their adverse and off-target effects. Available treatment for cancer patients has improved following a better understanding of the pathophysiology of cancer and advances in nanocarrier development. However, these traditional nanosystems lack innate targeting efficiencies, increased cellular internalization, and prolonged systemic circulation. Recent advances in the design of cutting-edge nanotechnology strategies like stimuli-responsive lipid nanoparticles (LNPs) have revolutionized clinical translation and use of LNPs in cancer treatment due to the efficiency of exogenous and endogenous factors to regulate drug release, increase cellular uptake, enhance systemic circulation, and promote tissue targeting. Beyond the brief introduction, this chapter provided an overview of challenges encountered in cancer therapy. It outlined the various lipid-based nanocarriers developed and deployed for cancer therapy. It enumerated and discussed the progress made in using different types of stimuli-responsive LNPs in cancer treatment. While it discussed the benefits and limitations of stimuli-responsive LNPs for cancer, it also provided insights into the safety considerations for clinical translation of stimuli-responsive LNPs in cancer.