High cell density cultivation (HCDC) is a key technology for the industrial production of biomolecules such as recombinant proteins, enzymes, and metabolites in bioreactors at high volumetric production rates. It is especially beneficial for biopharmaceutical production, including insulin, hormones, and vaccines. Despite its advantages, HCDC faces challenges like increased oxygen demand, heat generation, and by-product accumulation (e.g., acetate in E. coli), which can inhibit cell growth and waste nutrient resources. Effective feeding strategies and precise bioreactor monitoring and control of parameters such as feeding rate, pH value, oxygen, and biomass concentration are essential to address these issues. Fed-batch processes are most commonly used in HCDC for microorganisms, allowing controlled substrate feeding to maintain optimal specific growth rates (SGR) and avoid overflow metabolism. This chapter provides an overview of the concepts of different HCDC strategies. Challenges and limitations of HCDC systems are discussed.