Critical infrastructure (CI) faces a growing threat of cyber-attacks as digitalization expands across industries, necessitating robust cyber-security measures. This study focuses on the challenges of securing CI in Luxembourg, exploring both regulatory and organizational aspects. Semi-structured interviews with chief information security officers (CISOs) within Luxembourg’s CI sectors were conducted to gather insights. Thematic analysis revealed six key challenge themes: Regulatory Compliance, Industry Landscape and Adaptation, Resource Management, External Collaboration and Support, IT Infrastructure Management, and Operational Governance. The findings underscore the need for a comprehensive, multi-faceted approach involving international regulation alignment, streamlined reporting, enhanced national cyber-security support, government initiatives, and ongoing harmonization efforts across nations to address cyber-security challenges in critical infrastructure effectively.