Challenges in applying Monte Carlo sampling to biomolecular systems Abstract: this chapter, instead of reviewing the considerable progress made so far, discussse the obstacles that prevent the wider use of the Monte Carlo method for macromolecular simulations. Successful adoption of the Monte Carlo method for conformational sampling of macromolecular assemblies requires solution(s) to the following problems: (1) convince investigators that it is worth it; (2) devise move sets that generate large enough correlated changes that can be accepted with reasonable probability; (3) develop efficient treatment of non-pairwise additive potentials; (4) develop efficient treatment of long-range contributions to the system's energy; and (5) the efficient parallelization of the algorithm.