Transcriptional signaling networks are orchestrated and fine-tuned through multiple interactions of transcription factors with subsets of cofactors thereby assembling multiprotein complexes to negatively or positively balance transcriptional output. These mechanisms account for the large diversity of target genes but also for time and tissue specific gene regulations through single transcription factors such as SRF. One family of SRF coactivators that has attracted much attention is represented by the myocardin-related transcription factors (MRTFs). MRTFs themselves are controlled through interactions with a growing number of cofactors and transcriptional regulators. We recently identified SCAI (suppressor of cancer cell invasion), which can associate with MAL (MRTF-A) to modulate invasive cancer cell migration through regulation of beta1-integrin expression and function. However, SCAI is likely to have additional functions depending on the tissue environment and signaling program. Interestingly, SCAI not only inhibits MRTF-A but can also regulate the activities of other MRTFs such as myocardin, or the oncogenic OTT-MAL fusion protein. Thus, SCAI may act in very different conditions such as during cancer progression, development or cell differentiation.