Chemotherapy is one of the most conventionally used therapeutic interventions for treating various diseases. Chances of acquiring multidrug resistance in response to chemotherapeutic agents are exceedingly common among patients. Drug resistance arises mainly due to overexpression of efflux transporters such as P-glycoprotein and multidrug resistance-associated protein of the ATP-binding cassette superfamily of proteins, which significantly limits intracellular drug accumulation and drug activity. Although many approaches exist to overcome drug resistance, their uses are significantly limited in clinical practice. In this chapter, we demonstrate the superior functions of Pluronic-based technologies to overcome drug resistance. The present chapter highlights various aspects of Pluronic polymers, Pluronic conjugates, Pluronic nanotechnology, as well as their therapeutic implications for effective treatment strategies. We include the role of Pluronic polymers as a pharmaceutic excipient and drug delivery vehicle in this review. In addition, we highlight examples of Pluronic nanosystems that are currently in preclinical development, clinical trials, and clinically translatable formulations. Furthermore, a number of innovative Pluronic nano-designs of advanced therapeutics for future medicinal applications are presented. Collectively, the use of Pluronic-based nanoformulations discussed in this chapter suggests sensitization and prevention of drug resistance. Such an approach not only minimizes the dose required for treatment, but also minimizes the number of treatment cycles, which is useful in a clinical scenario.