The question that ultimately motivates most aerosol inhalation research is: for a given inhaled atmosphere, what health effects will result in a specified population? To attempt to address this question, quantitative research on inhaled aerosols has been performed for at least fifty years (Landahl et al, 1951). The physical factors that determine particle deposition have been determined, lung morphology has been quantified (particularly for adults), models of total particle deposition have been created and validated, and a large variety of inhalation experiments have been performed. However many basic questions remain, some of which are identified by the U.S. Committee on Research Priorities for Airborne Particulate Matter (NRC 1998a) as high-priority research areas. Among these are: What are the quantitative relationships between outdoor concentrations measured at stationary monitoring stations, and actual personal exposures? What are the exposures to biologically important constituents of particulate matter that cause responses in potentially susceptible subpopulations and the general population? What is the role of physicochemical characteristics of particulate matter in causing adverse health effects? As these questions show, in spite of significant progress in all areas of aerosol research, many of the most important practical questions remain unanswered or inadequately answered.In this chapter, we discuss the sources and magnitudes of error that hinder the ability to answer basic questions concerning the health effects of inhaled aerosols. We first consider the phenomena that affect the epidemiological studies, starting with studies of residential radon and moving on to fine particle air pollution. Next we discuss the major uncertainties in physical and physiological modeling of the causal chain that leads from inhaled aerosol concentration, to deposition in the airway, to time-dependent dose (that is, the concentration of particles at a given point in the lungs as function of time), to physiological effects, and finally to health effect.