In this study we reported the effect of shear stress, protein adhesion, temperature, secondary interactions and gas core on microbubble stability which are the main reasons of microbubble dissolution in body. Air filled DSPC/PEG40St microbubbles were examined under shear stress. Increasing PEG40St molar ratio increased the resistivity microbubbles against shear stress. To investigate effect of emulsifier type, microbubbles were produced by mixing DSPC with DSPE-PEG1000, DSPE-PEG2000 and PEG40St at 5:5 molar ratio and PEG40St microbubbles were more stable since it provide better curvature to microbubble shell due to its shape. Shear stress experiments were also performed at different temperatures. With increasing temperature microbubbles became less stable since van der Waals interactions between shell components decreased. When microbubbles were filled with perfluorocarbon, since its solubility is lower and more hydrophobic than air, the stability of microbubbles against shear stress increased. Protein adhesion to microbubble shell was investigated by Langmuir Blodgett (LB) and Surface Plasmon Resonance techniques. Both techniques showed that, as the PEG40St molar ratio and packing density increased, protein adhesion decreased. Secondary interactions between shell components were examined via LB technique and visualized via Brewster Angle Microscopy. As third component to DSPC/PEG40St mixture, StGly, StNH2, DSPS, DSTAP was added and ternary mixtures were generally miscible. Since StGly and StNH2 has single tail, they cannot provide curvature in bubble surface. DSPS and DSTAP mixtures may be recommended drug delivery.