Modern integrated circuits (ICs) require a complex, outsourced supply-chain, involving computer-aided design (CAD) tools, expert knowledge, and advanced foundries. This complexity has led to various security threats, such as Trojans inserted by adversaries during outsourcing, but also run-time threats like physical probing. Our proposed design-time solution, DEFense , is an extensible CAD framework for holistic assessment and proactive mitigation of multiple prominent threats.