At the dawn of the 20th century, the change in the scientific, political and cultural attitudes towards malaria was the result of the discovery of the theoretical simplicity of the malaria transmission cycle and of the possibility to interrupt it, by avoiding the contacts between people and mosquitoes. The 'mosquito hypothesis', suggested already in the 1880s, had to be included into a coherent scientific theory, in which a fundamental part was played by the concept of specificity. The paper analyses the Italian contribution to this scientific change and the epistemological aspects of the debate between Ronald Ross and Battista Grassi about their respective role in the discovery of the human malaria transmission cycle. This debate has been often interpreted in sociological or psychological terms. However, behind the dispute there is a different definition of what is a scientific explanation in biological sciences and in particular in parasitology. This point is made clear by the analysis of four different theoretical problems implied in the discovery of the transmission cycle: the concept of specificity, the comparative method in parasitology, the specificity of the life-cycle of parasites and vectors, and the role of the analogical reasoning in science and medicine.