In the course of drug development, a staggeringly small number of drugs actually make it through the discovery and development pipeline and onto the market. Roughly half of these candidates fail due to issues with efficacy and/or safety. Clinical assessment for potential QT effects would likely require a separate study or cohort within the planned clinical study of the combination. Nonclinical combination toxicity studies are best utilized to demonstrate the safety of the combination and identify potential hazards rather than allow for a true risk assessment. This chapter reviews the relevant health authority guidance regarding the nonclinical development of combination products and proposes a scientific approach for determining the need for a nonclinical combination toxicity study. Clinical development timelines often impact a sponsor’s ability to get health authority feedback on their nonclinical plans for supporting a drug combination development program. The value of a nonclinical combination toxicity study even before it is conducted is debatable and a matter of perspective.