Laser and instrument systems used for space flight have extreme requirements for cleanliness. Many of these systems specify or require cleanliness target values approaching one monolayer of non-volatile residue (NVR) or even less in some cases. This opens up a completely new series of challenges that are added to the challenges facing contamination control and contamination analysis personnel. As the amount of molecular contamination on a surface approaches zero, the behavior of the contaminant changes. These behavioral changes require knowledge of the surfaces and the contamination beyond whether bulk material is soluble in the solvent. As the thickness of the contamination drops below a few monolayers, the bulk properties become nearly irrelevant. Knowledge of the interactions of the contaminant with the surface becomes critical. This includes both the equilibrium and kinetics of the surface adsorption. The paper will address the fundamental physical, procedural, philosophical, and technical aspects of cleaning surfaces to the monolayer level.