The X-linked gene Rnf12 encodes the ubiquitin ligase RLIM/Rnf12 which serves as a major sex-specific epigenetic regulator of female mouse nurturing tissues. Early during embryogenesis, RLIM/Rnf12 expressed from the maternal allele is crucial for the development of extraembryonic trophoblast cells. In contrast, in mammary glands of pregnant and lactating adult females RLIM/Rnf12 expressed from the paternal allele functions as a critical survival factor for milk producing alveolar cells. While RLIM/Rnf12 is detected mostly in the nucleus, little is known about how and in which cellular compartment(s) RLIM/Rnf12 mediates its biological functions. Here, we demonstrate that RLIM/Rnf12 protein shuttles between the nucleus and cytoplasm and that this is regulated by phosphorylation of serine S214 located within its nuclear localization sequence (NLS). We show that shuttling is important for RLIM to exert its biological functions, as alveolar cell survival activity is inhibited in shuttling-deficient nuclear or cytoplasmic RLIM/Rnf12. Thus, the regulated nucleo-cytoplasmic shuttling of RLIM/Rnf12 coordinates cellular compartments during alveolar cell survival.