The first years of the 21st century have seen an unparalleled progress in biomedical sciences. Several dogmata that haunted scientific debate for decades were easily abandoned, and there is a fundamental shift away from eminence-based toward evidence-based assessment of preclinical models, probing their true value in predicting clinical outcomes of human diseases. Likewise, several new approaches, e.g., stem cell-based, diseases-in-a-dish and organs-on-a-chip and lab-on-a-chip technologies have revitalized the domain of alternatives to animal experimentation. In our review, we portray these and other efforts to bring forth relevant and ethically inoffensive models of human diseases.