Industrial and sport protective clothing (PC) is governed by protection requirements and sport clothing is generally selected on the basis of performance and comfort. The impact of PC on performance is determined by the nature of the work or sport, the metabolic rate required, the ambient environment, and the characteristics of the PC. The chief ergonomics challenge of PC is when moderate to high work rates must be performed in moderate to hot ambient environments. Comfort is typically subjectively measured and impacts performance. Comfort is multifactorial and dynamic rather than static. Sport clothing design is chiefly concerned with maximizing heat and moisture loss and comfort; however, attempts to use synthetic fabrics to increase comfort and heat dissipation have generally not been successful. Future innovations may include protective and sport clothing that responds to the environment, and that features integrated cooling systems with greater cooling capacity and practicality for mobile workers and sportsmen. A brief review of key challenges in the ergonomics of PC and sport clothing is presented along with potential directions for advancing ergonomics and comfort.