Since almost 4 decades, connexins have been discussed as important regulators of embryogenesis. Several different members of the gene family can be detected in the preimplantation embryo and during gastrulation. However, genetically engineered mice deficient for every connexin expressed during early development are available and even double-deficient mice were generated. Interestingly, all of these mice complete gastrulation without any abnormalities. This raises the question if the role of connexins has been overrated or if other gene family members compensate and mask their importance. To answer this question, embryos completely devoid of any gap junctional communication need to be investigated. This is challenging because a variety of connexin genes are co-expressed and some null mutations lead to a lethal phenotype. In addition, maternal connexin transcripts were described to persist until the blastocyst stage. In this review, we summarize the current knowledge about the role of connexins during preimplantation development and in embryonic stem cells. We propose that the use of pluripotent stem cells, trophoblast stem cells, as well as artificial embryo-like structures and organoid cultures in combination with multiplex CRISPR/Cas9-based genome editing provides a powerful platform to comprehensively readdress this issue and decipher the role of connexins during lineage decision, differentiation, and morphogenesis in a cell culture model for mouse and human development.