Human factors engineering (HFE), such as other engineering disciplines involved in plant design, cannot be considered retroactively. The engineering principles and methods derived from deep knowledge of the cognitive and perceptual capabilities and limitations of the plant’s “human element” are applied instead throughout the plant design. Focusing HFE efforts, the plant’s HMI is designed to ensure effective and error-free performance of the monitoring, control, and administrative tasks allocated to the control-room crew. A project’s HFE program prescribes three main steps (1) The task analysis and the analyses of plant monitoring and control functions to identify those to be performed manually (all others are performed automatically, or in a combination of manual and automatic, while still manually monitored) and determine in turn the HMI inventory of information displays, controls, alarms, and operating procedures required to support their performance. (2) The guided design of the plant’s HMI, ensuring its compliance with HFE principles and the completeness and correctness of the task support it provides. (3) The subsequent evaluation of operator performance, trained to follow the operating procedures and use of the HMI. Authors’ experience shows that the three following required steps pose challenges to project execution: (1) the acquisition and analysis of the multidisciplinary functional requirements (related to plant monitoring and control); (2) the likely interdisciplinary analysis and how fulfillment of these requirements shall be allocated to I&C automation systems or operators (or both); and (3) the HFE-guided HMI design and validation. An additional fourth challenge poses a timely and cost-effective application of HFE to I&C engineering, which can be achieved by adequate planning and project management procedures. This paper aims to summarize some of our industrial experiences gained in new builds and modernization projects of nuclear power plants around the world.