Preservation of mitochondrial quality is paramount for cellular homeostasis. The integrity of mitochondria is guarded by the balanced interplay between anabolic and catabolic mechanisms. The removal of bio-energetically flawed mitochondria is mediated by the process of mitophagy; the impairment of which leads to the accumulation of defective mitochondria which signal the activation of compensatory mechanisms to the nucleus. This process is known as the mitochondrial retrograde response (MRR) and is enacted by Reactive Oxygen Species (ROS), Calcium (Ca 2+ ), ATP, as well as imbalanced lipid and proteostasis. Central to this mitochondria-to-nucleus signalling are the transcription factors (e.g. the nuclear factor kappalight-chain-enhancer of activated B cells, NF-κB) which drive the expression of genes to adapt the cell to the compromised homeostasis. An increased degree of cellular proliferation is among the consequences of the MRR and as such, engagement of mitochondrial-nuclear communication is frequently observed in cancer. Mitophagy and the MRR are therefore interlinked processes framed to, respectively, prevent or compensate for mitochondrial defects. In this review, we discuss the available knowledge on the interdependency of these processes and their contribution to cell signalling in cancer.