An increasing awareness of life support system reliability has been noticed in the aerospace community as long-term space missions become realistic objectives. However, system reliability requirements are subject to many constraints, particularly the mission cost. This paper presents a coupled analysis of cost and reliability for optimal exploration life support system design. Simulation tools capable of representing complex dynamical systems with configurable uncertainties are utilized for reliability prediction in comparison with the classical reliability prediction approaches. The motivation of this work emerged from the understanding of the conventional reliability prediction approaches and the currently proposed life support system reliability designs for CEV, Lunar Outposts, and other long-term missions. Literature review indicates a significant knowledge gap in the accurate evaluation of the reliability of environmental control and life support systems. Such a gap is believed to result from the unique characteristics associated with ECLSS and other environmental systems. The results presented in this paper consider the difference between reliability prediction results obtained from the traditional approaches and the newly developed method which has been adjusted to address the new challenge. Simulation and statistical analysis are utilized to quantify the impact of buffering capacity, contingency plans, and maintenance strategies on reliability prediction for ECLSS. A brief investigation of the system cost will also be performed to provide preliminary suggestions for balancing system reliability requirements and the associated costs.