Coordinated smooth muscle contraction is critical for force production and proper functioning of numerous organ systems. Activation at the myosin motor domain via phosphorylated myosin light chain (phospho-MLC) remains the primary signal to initiate contraction, but it is now appreciated that there are additional force modulators also present in smooth muscle. One particularly well studied modulatory protein is Caldesmon (CaD), which has been implicated in controlling contractile force in vascular smooth muscle, however little is known of CaD's physiological role in vivo. Studies in vitro have shown that CaD inhibits actomyosin interactions and that this effect is reversed after phosphorylation, allowing for greater force propagation. Since a number of gastrointestinal (GI) tract and vascular disorders are known to be a result of aberrant force production, closely monitoring CaD's functional properties may provide insight into common contractile defects. We took advantage of the transparent nature of the intestine in larval zebrafish to study CaD's effect on smooth muscle contraction in a vertebrate model. We initiated these studies by examining propulsive peristalsis in the larval intestine after knockdown of endogenous smooth muscle CaD protein. We next measured the role of CaD in the absence of phospho-MLC to better understand its function in disease states where myosin activation is perturbed. Using extensive live imaging analysis, we show that disrupting CaD function within intestinal smooth muscle can significantly increase GI motility, with and without phospho-MLC, highlighting CaD's ability to independently modulate contractile force. In addition, previous work on a mutant, meltdown (mlt), in our lab has uncovered a smooth muscle myosin (myh11) mutation leading to increased contractile force and premature CaD phosphorylation. Interestingly, in the mlt mutant intestinal epithelial invasion was observed pointing to the unique role for force propagation in initiating cell invasion. We show that CaD is necessary for mlt epithelial invasion to occur, as knockdown of CaD causes the invasive phenotype in heterozygous mlt, which otherwise appear wild type. To gain a better understanding of the crosstalk between muscle contraction and epithelial invasion, we performed a genetic screen for modifier mutants of the mlt phenotype. From the screen, we discovered two enhancer mutants of mlt that contained missense mutations in unique protein domains of MYH11 that alter the contractile function of smooth muscle. These mutations (S237Y and L1287M) occur in both the motor domain and helical tail domain of the protein, suggesting that alterations in distinct regions of myosin can result in abnormal contraction and potentially lead to invasion in underlying cells. Since a number of myosin mutations have been implicated in vascular disease and colon cancer, these studies provide insight into the diversity and mechanistic consequences of mutated myosin in altering smooth muscle contraction and epithelial cell invasion.