After a decade of active research, pressure is mounting for clinical translation of nanomedicines. However, to enable success in the clinic, it is important to understand the factors that can pose challenges. For example, reduction in adverse effects alone might not be enough of a driver today for clinical translation. The benchmark for clinical translation will be increased efficacy, a significant challenge to overcome if nanomedicines are developed only from a drug delivery perspective. Success in clinics will therefore require a re-examination of the design of nanomedicines, including challenging current dogmas. What can we learn from translational experience with recently approved antibody-drug conjugates, which like nanomedicines is another approach to deliver chemotherapy agents selectively to the tumors? Nanomedicines can address some of the emerging challenges in cancer chemotherapy, including heterogeneity and adaptive resistance, which can offer unique translational opportunities. This article addresses some of these themes and strategies that can facilitate translation of nanomedicines to the clinic.