Development of intrinsic and acquired drug resistance in cancer is a significant clinical challenge for effective therapeutic outcomes. Multidrug resistance (MDR) in solid tumors is especially difficult to overcome due to the many different factors that influence clinically manifested refractory disease. Genetic profiling of MDR tumors can provide for more specific control through RNA interference (RNAi) therapy. However, there are multiple barriers to effective in vivo delivery of functional nucleic acid constructs, such as small interfering RNAs (siRNAs) and micro RNAs (miRNAs or miRs). In this review, we have briefly described the principles and mechanisms based on the RNA interference phenomenon and the barriers to its successful clinical translation. The principles of active and passive tumor targeting using nanoparticles systems are also discussed. Furthermore, illustrative examples of miRNA, siRNA, and gene-drug combination delivery using nanoparticle systems that have shown promising potentials for the treatment of diseases such as MDR cancers are covered.