It is long known that stem cell differentiation correlates with a lengthening of the cell cycle, in particular G1. Moreover, models were proposed for mammalian embryonic, neural and hematopoietic stem cells whereby lengthening of G1 is a cause, rather than a consequence, of differentiation. These models are based on the concept that time, i.e., G1 length, may be a limiting factor for cell fate change to occur because differentiation factors require time in order to trigger a physiological response. Despite the many correlative studies, this hypothesis proved difficult to demonstrate because most trophic, signaling or transcription factors involved in stem cell differentiation may concurrently, but independently, also have an effect on cell cycle progression, which calls for a thorough review on the differentiation role of genes whose best characterized and long established function is exclusively to control G1. For this reason, we here focus our attention on the effects that the core molecular machinery controlling G1 progression, i.e., the G1-specific cyclin dependent kinase (cdk)/cyclin complexes, have on stem cell differentiation. In particular, we will discuss the effects of G1-cdks/cyclins on differentiation of embryonic, neural and hematopoietic stem cells during development and adulthood, for which a role of G1 length has been proposed.