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Despite the importance for their health and well-being of children’s acquiring knowledge and understanding of disease, surprisingly little work has been done to compare children’s thinking about different diseases at different ages to determine whether and how thinking about familiar diseases shapes thinking about newly encountered diseases. The present study reports a new analysis of interviews with 156 children that were conducted in 1992, when AIDS represented a new and life-threatening but not well understood health threat.  The aim was to compare thinking about the causality of a familiar disease, influenza, and a then-unfamiliar disease, AIDS, among third, fifth, and seventh graders. Comparisons of the two diseases and three grade levels focused on: (a) level of understanding based on cognitive-developmental theory and (b) three features defining children’s intuitive theories of disease (a biological ontology or vocabulary, causal propositions featuring an invisible germ or virus, and logical coherence). Scores on all four resulting summary measures and on all but one of eight causal propositions collectively constituting a scientific explanation of each disease, increased with age, with growth especially pronounced from third grade to fifth and seventh grades. Summary scores were moderately intercorrelated, both within each disease and across the two diseases. Folk beliefs about cold weather causing flu and casual contact causing AIDS declined with age. Levels of knowledge and understanding of the two diseases were more often similar than different. However, children’s thinking about flu was ahead of their thinking about AIDS in some respects, especially among the youngest children and especially with respect to symptomology. At the same time, exposure to information during the AIDS epidemic appeared to enable children describing AIDS causality to replace the generic term germ used for flu with the more specific term virus and to better understand that a person must have a disease or its pathogen to transmit it, that the causal agent for a disease is disease-specific, and that the body resists germs and viruses. Implications for better understanding the development of disease concepts and filling gaps in children’s knowledge and understanding in the era of COVID-19 are discussed.