Nanoparticles have recently emerged as a promising class of carriers for the co-delivery of multiple drugs. Combination therapies of small-molecule drugs are common in clinical practice, and it is anticipated that packaging into single macromolecular carriers will enable drug release in precisely balanced ratios and rates and in selectively targeted tissues and cells. This vast level of pharmacological control is intriguing, especially from the perspective of tailoring personalized treatments with maximized therapeutic synergy for individual patients. Here, we discuss promising formulations and opportunities to employ advanced screening tools and new animal models of disease that can improve chances for successful clinical translation.