Elimination of metabolic flux imbalances in microbial cell factories is an important part in the establishment of viable biotechnological production processes. However, due to the high complexity of cellular metabolism, the limited a priori knowledge about the majority of production pathways and a lack of forward design standards, metabolic engineers strongly rely on empirical screening methodologies to achieve the required improvement of cell behavior. Combinatorial pathway engineering provides an interesting tool to identify global solutions for intricate pathways, but methods for the reduction of combinatorial library size are inevitably required to restrict the experimental effort to an affordable size. Here we review recent advances from this field by scrutinizing commonly applied diversification methods and highlighting crucial strategies for the minimization of experimental effort.