The pathway of mitochondrial-specific autophagy (mitophagy, defined here as the specific elimination of mitochondria following distinct mitochondrial injuries or developmental/metabolic alterations) is important in health and disease. This review will be focussed on the earliest steps of the pathway concerning the mechanisms and requirements for initiating autophagosome formation on a mitochondrial target. More specifically, and in view of the fact that we understand the basic mechanism of non-selective autophagy and are beginning to reshape this knowledge towards the pathways of selective autophagy, two aspects of mitophagy will be covered: (i) How does a machinery normally working in association with the endoplasmic reticulum (ER) to make an autophagosome can also do so at a site distinct from the ER such as on the surface of the targeted cargo? and (ii) how does the machinery deal with cargo of multiple sizes?