Mesenchymal stem cells (MSCs) are pluripotent cells which can differentiate into several distinct lineages, such as chondrocytes, adipocytes and myofibers. It has been reported that the lineage-specific transcriptional factors including Runt related transcription factor 2 (RUNX2), Peroxisome proliferator-activator receptor gamma (PPARgamma) and Myogenic differentiation 1 (MyoD) may play key regulatory roles among the differentiation of MSCs. Recently, researches have confirmed that the Hippo pathway impacts the differentiation fates of MSCs through regulating the activity of line- age-specific transcription factors by the Hippo pathway effectors Tafazzin (TAZ) and/or Yes-associated protein (YAP). The interaction between TAZ and RUNX2 boosts the osteogenic processes and promotes MSCs differentiating into osteoblast lineage. However, PPARgamma binding to TAZ may inhibit the adipocytes differentiation, and thus overexpression of TAZ in mesenchymal stem cell-like cells increases the expression of myogenic genes and hastens myofiber formation through a MyoD-dependent manner. Moreover, other signaling pathways (such as BMP-2, TNF-alpha, Eph-Ephrin, etc.), small molecules (KR62980, TM-25659, etc.), and mechanistic stimuli can also affect the fate by regulating the activity of TAZ/YAP. In this review, we summarized the signaling pattern of Hippo pathway and the function mechanism of TAZ and/or YAP by enumerating their interaction to several lineage-specific transcriptional factors and relationship with other signal pathways during MSCs differentiation.