Remodeling of the extracellular matrix (ECM) plays crucial roles in both tumor progression and organ development. However, the molecular mechanisms that regulate ECM remodeling are not fully understood. In zebrafish, asymmetric migration of the epithelial lateral plate mesoderm (LPM) displaces the gut to the left, leading to the correct placement of the liver and pancreas. The bHLH transcription factor Hand2 is expressed in the anterior LPM as well as its mesenchymal derivatives. In order to observe these tissues at higher resolution, we generated a transgenic line that expresses GFP under the control of the hand2 regulatory regions. By confocal imaging, we show that during the process of gut looping, Laminin is distributed along the LPM/gut boundary, and appears to be degraded by the Hand2-expressing cells as they undergo asymmetric migration. Laminin degradation is required for LPM migration and is dependent on matrix metalloprotease (MMP) activity. Loss of Hand2 function causes reduced MMP activity and prolonged Laminin deposition at the LPM/gut boundary. Consequently, asymmetric LPM migration and leftward gut looping fail to occur in these embryos. Our study reveals an unexpected role for Hand2, a transcription factor that controls cell specification and differentiation, in modulating ECM remodeling during organ morphogenesis.