A model-based approach for optimization and cascade control of dissolved oxygen partial pressure (pO2) and maximization of biomass in fed-batch cultivations is presented. The procedure is based on the off-line model-based optimization of the optimal feeding rate profiles and the subsequent automatic pO2 control using a proposed cascade control technique. During the model-based optimization of the process, feeding rate profiles are optimized with respect to the imposed technological constraints (initial and maximal cultivation volume, cultivation time, feeding rate range, maximal oxygen transfer rate and pO2 level). The cascade pO2 control is implemented using activation of cascades for agitation, oxygen enrichment, and correction of the preoptimized feeding rate profiles. The proposed approach is investigated in two typical fed-batch processes with Escherichia coli and Saccharomyces cerevisiae. The obtained results show that it was possible to achieve sufficiently high biomass levels with respect to the given technological constraints and to improve controllability of the investigated processes.