Crop researchers have developed a number of hybrids and varieties exhibiting superiority in desired traits (e.g., yield, quality, and resilience) via exploitation of heterosis in breeding programs. Controlled pollination has always been a Herculean challenge in the development of crop hybrids as well as field-scale production of hybrid seeds. In this context, cytoplasmic male sterility (CMS) has served as a robust genetic mechanism to control pollination in heterosis breeding and hybrid seed production in crop plants. CMS, manifested as production of nonfunctional pollen, results from compromised harmony between the organelle and nuclear genomes. Research has established mitochondrial ORF (Open Reading Frame) as causal genes for inducing CMS in several plant species. The restorer of fertility (Rf) genes residing in the nucleus overcomes the action of CMS-causing mitochondrial genes, thus resuming pollen fertility in the F1 hybrids. Thus, the hybrid production using CMS technology entails three components: CMA line (A) line, maintainer (B) line, and restorer (R) line. Genetic mapping and cloning of Rf genes in combination with evolving landscape of omics technologies in plants have provided new insights into CMS-Rf system. More recently, sequence-specific nucleases combined with mitochondrial targeted signals (mito-TALENs) have been deployed to edit mitochondrial genomes in plants, thus offering concrete evidence supporting mitochondrial role in CMS occurrence. This is notable given the fact that evidence linking mitochondrial genes with CMS was previously lacking in crop plants. Knowledge of the genetic and molecular basis of CMS and fertility restoration is imperative to understand the nucleo-cytoplasmic crosstalk and for breeding modern crop hybrids with better yield, quality and resilience.