<p>Programmed cell death (PCD) is a regulatory process essential for the development and maintenance of multicellular integrity. While the objectives and execution of PCD are somewhat similar between plant and animal cells, there are some significant differences from the mechanistic viewpoints for the executions and regulations to fulfill PCD. In animal cells, PCD is initiated by either extrinsic or intrinsic pathways under the influence of different stimuli involving several death receptor proteins that follow the convergence of both pathways at the time of caspase activation which eventually leads to cell death. In contrast, plant cells lack death receptor proteins and cell death <i>in-planta</i> is independent of caspases. However, plants do involve a distant relative of caspases called metacaspase in the cell death execution machinery. However, a trans-kingdom approach to studying the cell death mechanisms in plants and animals that involves an in-depth investigation of the molecular and genetic similarities and differences between the two different systems has been sporadically used as indicative of a potential approach in identifying the commonalities among PCD pathways of both the kingdoms. In light of recent research, some common executioner genes were identified related to the induction of PCD signaling suggesting such approaches may provide valuable insights into the evolution and function of PCD in multicellular organisms. Through this review article, we discuss the comparative molecular mechanisms and genetic involvement of the PCD process in plant and animal cells. We discussed the importance of multi-cellularity and cell–cell communication patterns to make PCD a unique cell death process for only plant and animal kingdoms may not implicate for other kingdoms of life. Moreover, we advocate the significance of the moonlighting proteins which may add substantial value in comprehending the fundamental process of PCD from the evolutionary perspective.</p>