Cancer is the second leading cause of mortality among nontransmissible diseases globally. Despite the advances in chemotherapy, the insufficient drug selectivity against cancer cells poses multiple challenges to this treatment modality, such as severe adverse effects and multidrug resistance. The pharmacokinetic properties of many chemotherapy agents (e.g., limited solubility) also restrict modes of administration options. Clearly, newer therapeutic strategies are required. Nanomedicine, particularly, is an innovative approach: drug encapsulation within nanoparticles (NPs) has the potential to enhance tumor selectivity, reduce systemic adverse effects, combine multiple drugs within the same nanoplatform, and enhance drug pharmacokinetics/biocompatibility. However, nano-therapies targeting directly the tumor cells exhibit certain constraints due to the heterogeneous expression of the target molecule between individuals or within the same tumor, expression of the target moiety on healthy tissues, and limited tumor penetration. The tumor microenvironment (TME) represents an optimal target due to its intrinsic physicochemical conditions (e.g., hypoxia, low pH, high oxidative stress, enzyme overexpression), which differ from the ones present in healthy tissues. Therefore, NPs can be sensitized to the TME stimuli for selective drug delivery. This chapter will discuss the TME stimuli in the context of nanoplatform-based drug delivery. In addition, novel TME-responsive, nanoplatform-based therapies to overcome conventional chemotherapy challenges will be discussed.