The cell membrane defines the boundaries for cells and hence acts both as a first line of defense against pathogen invasion and as a significant barrier for the effective delivery of medical therapeutics. The fusion of membranes and the controlled transport of materials across cells involve the formation of transient membrane pores, while the resistance against cell lysis (rupture) is determined by the stability of the membrane against the formation of pores, e.g., during osmotic swelling.   Because the softness of the material, thermal fluctuations are important and many of the membrane processes of interest are thermally-nucleated (rare) events.  In this talk, I will describe a method we developed for exploring a wide range of challenging and previously intractable membrane nucleation problems both in the absence and in the presence of particles. Our method combines the string method with a dynamic self-consistent field theory into an efficient “on-the-fly” algorithm for the determination of the minimum free energy path in the membrane pore formation, rupture, and nanoparticle translocation.  For a uniform membrane in the tension regime where nucleation can occur on experimentally relevant time scales, the structure of the critical nucleus is between a solvophilic stalk and a locally thinned membrane. Classical nucleation theory fails to capture these molecular details and significantly overestimates the free energy barrier.  The presence of a positively charged nanoparticle can lead to a significant reduction in the barrier to pore formation or rupture.  Depending on the particle size, charge and hydrophobicity, we find that there can be at least three competing pathways: (1) particle-assisted membrane rupture, (2) particle translocation, and (3) particle insertion into a metastable pore followed by membrane rupture.  The implications of these results on the endosomal escape mechanism in the context of polymer-based gene delivery systems will be discussed.