Malfunction of autophagy, the process that mediates breakdown and recycling of intracellular components in lysosomes, has been linked to a variety of human diseases. As the number of pathologies associated with defective autophagy increases, emphasis has switched from the mere description of the status of autophagy in these conditions to a more mechanistic dissection of the autophagic changes. Understanding the reasons behind the autophagic defect, the immediate consequences of the autophagic compromise and how autophagy changes with the evolution of the disease has become a ‘must,’ especially now that manipulation of autophagy is being considered as a therapeutic strategy. Here, we comment on some of the common themes that have emerged from such detailed analyses of the interplay between autophagy and disease conditions.