According to the World Health Organization (WHO), cancer is a leading cause of death worldwide. Despite the availability of various chemotherapeutic agents, delivery of such drugs to the tumor site in a spatio-temporally controlled manner is still an unmet need. Stimuli-responsive polymeric nanoparticulate delivery systems showed improved therapeutic efficacy as compared to conventional systems, due to their unique properties such as cancer tissue-specific targeting and/or stimuli-responsive drug release within the tumor microenvironment. These nanoparticles can respond to various endogenous and/or exogenous stimuli, thereby releasing entrapped drugs at the tumor site. This chapter discusses the characteristics of tumor microenvironment, such as alterations in oxygen concentration (hypoxia), pH, redox state, and oxidative stress of the cancer cells, that provide insights for stimuli-responsive targeted drug delivery. Further, this chapter mentions about widely explored exogenous stimuli, such as magnetic fields, ultrasound, light, and temperature, that are employed for targeted therapy. In addition, targeted drug delivery strategies that explored mono- or multi-stimuli responsive polymeric nanoparticulate drug delivery systems have been mentioned. In a nutshell, this chapter provides a deep understanding of cancer-targeted stimulus-responsive polymer nanoparticles that solve the challenges encountered in conventional chemotherapy.