Studies of closed environments, Sick Building Syndrome (SBS) and NASA's Water Recovery Test reveal key issues in interdisciplinary problem-solving. Basic scientific issues include contamination control, microbial management, and passive biocides. Technological development issues include limits of uncertainty in closed biological systems, the information management and control required to support such systems, and the interface between physical-chemical (P/C) and biological life support elements. Research has indicated the limits of P/C systems in the face of biological challenge. The technological demands will drive the engineering design requirements for appropriate technology. The final engineering challenge will be designs which can be supported, augmented, and replicated by Lunar and Mars materials.With the need to create air-tight, long-use facilities, Life Support System (LSS) designs must meet similar challenges to those of closing building air-handling systems. Although many obvious contributors to SBS are not present in the Space Shuttle and will be excluded from space stations, any future space habitat will face a complex set of pressures from its recycling systems, its trace contaminants, and its inherent microflora.This paper reviews LSS closure work and lessons learned from the SBS field to highlight LSS design issues. The analogies between these two efforts will become apparent as extended-duration spaceflight becomes routine. Live-in/ground-based tests of these systems are imperative before they go into orbit. When decrements in crew performance are ascribed to SBS-equivalents, designers must differentiate causality from plausibility, and be prepared to alter design only when the evidence warrants. Total system integration testing cannot be provided by paper studies or math models, especially at the interface of biology and engineering.