Thiazole and thiadiazole analogues have been recently proposed as a novel promising class of adenosine A1 and A3 receptor antagonists. When appropriately modified, they show selectivity toward A1 or A3 receptors, which results in a variety of therapeutic potentialities of these ligands. In this work, we carried out a QSAR study on thiazole and thiadiazole analogues as antagonists for adenosine A1 and A3 receptors. To develop reliable models, we focused attention on any possible pitfalls of each step of QSAR process and approached each stage following accurate procedures. Application of datasets by using CODESSA software led to QSAR equations based on three and four descriptors for the adenosine A1 and A3 receptor ligands, respectively. The obtained models allowed us to understand the main structural features that strongly correlate with the target property.