Several systemic weaknesses make IT systems inherently difficult to defend from a cybersecurity perspective. These weaknesses include vulnerabilities in computer code, misaligned incentive structures, a lack of understanding of critical interdependencies, and difficulties in managing the supply chain for both hardware and software. Although current cybersecurity practices can reduce the risk from these threats, substantially altering the balance between intruders and defenders will require sustained research and development (R&D) activity. In many cases, due to the fundamental, broad, long-term nature of the problem, the Federal government is the right sponsor for such R&D. Research and development funding in any or all the following areas would help address a critical systemic weakness: supply chain; secure coding practices; automation, artificial intelligence and machine learning; incentives; encryption and key management; understanding interdependencies and incentives; defenses against data manipulation; and workforce training.