The aim of this study was to quantify the physical demands of a simulated firefighting circuit and to establish the relationship between job performance and endurance and strength fitness measurements. On four separate days 41 professional firefighters (39 ± 9 yr, 179.6 ± 2.3 cm, 84.4 ± 9.2 kg, BMI 26.1 ± 2.8 kg/m2) performed treadmill testing, fitness testing (strength, balance and flexibility) and a simulated firefighting exercise. The firefighting exercise included ladder climbing (20 m), treadmill walking (200 m), pulling a wire rope hoist (15 times) and crawling an orientation section (50 m). Firefighting performance during the simulated exercise was evaluated by a simple time-strain-air depletion model (TSA) taking the sum of z-transformed parameters of time to finish the exercise, strain in terms of mean heart rate, and air depletion from the breathing apparatus. Multiple regression analysis based on the TSA-model served for the identification of the physiological determinants most relevant for professional firefighting. Three main factors with great influence on firefighting performance were identified (70.1% of total explained variance): VO2peak, the time firefighter exercised below their individual ventilatory threshold and mean breathing frequency. Based on the identified main factors influencing firefighting performance we recommend a periodic preventive health screening for incumbents to monitor peak VO2 and individual ventilatory threshold.