Transmembrane protein 161b (Tmem161b) was recently identified in multiple high-through-put phenotypic screens, including in fly, zebrafish, and mouse. In zebrafish, Tmem161b was identified as an essential regulator of cardiac rhythm. In mouse, Tmem161b shows conserved function in regulating cardiac rhythm but has also been shown to impact cardiac morphology. Homozygous or heterozygous missense mutations have also recently been reported for TMEM161B in patients with structural brain malformations, although its significance in the human heart remains to be determined. Across the three model organisms studied to date (fly, fish, and mouse), Tmem161b loss of function is implicated in intracellular calcium ion handling, which may explain the diverse phenotypes observed. This review summarises the current knowledge of this conserved and functionally essential protein in the context of cardiac biology.