Health technology assessments in the USA often model the costs and benefits for a given therapy using an average across all healthcare payers. The fragmented nature of the US healthcare system, involving multiple payers with varied health plans, makes payer- or patient-specific costs difficult to determine. For some public payers in which eligibility and coverage is tied to poverty or disability status, the financial incentives governing costs and benefits may be very different than for other payers. For example, in mental health and substance use, an effective intervention could alleviate poverty or disability status and modify program eligibility, creating substantial savings for public payers. The savings to public payers would not be reflected in health technology assessments that do not take a public payer perspective. This article discusses the role of health technology assessment in mental health and substance use and explores the opportunity to model public payers separately in order to capture eligibility effects—potentially driving more public investment in human development.