The ability of microbial enzyme systems to completely hydrolyze the structural polysaccharides of plant cell walls has been the focus of extensive research. While many enzymes have been identified and characterized, no single mechanism for total lignocellulosic saccharification has been established. The heterogeneous nature of lignocellulosic matrices makes it difficult to fully understand the interactions between enzyme complexes and these substrates. The efficacy of enzymatic complexes to hydrolyze these substrates is closely linked to the structural characteristics of the substrate and the modifications that occur during saccharification. This review aims to illustrate the potential enzymatic and structural limitations that influence the complete hydrolysis of lignocellulosic polysaccharides. Despite extensive research, our understanding of how enzymes completely hydrolyze lignocellulosic substrates remains incomplete. Substrate complexity and the need for multiple enzymes to effectively and completely hydrolyze these substrates have been well established. The repeating β-1–4 linking cellobiose unit is not indicative of the complex arrangement of the substrate at the fibril, fiber, and wood/pulp levels. Although tools like molecular biology and protein engineering have helped elucidate the role of some enzymes in the synergistic attack of lignocellulosic substrates, our understanding of basic mechanisms such as enzyme regulation, kinetics, and the extent of true synergism is still lacking. Research has focused on identifying the limiting factors in decreased hydrolysis rates, which are traditionally divided into two groups: those related to the structure of the substrate and those related to the mechanisms and interactions of the cellulase enzymes. Various model cellulose substrates have been used to study the mechanism of action and interaction of individual cellulase enzymes and the effect of substrate characteristics on the rate and efficiency of enzymatic hydrolysis. These include Avicel, solka floc, filter paper, cotton, valonia cellulose, phosphoric acid swollen cellulose, bacterial microcrystalline cellulose, and soluble cellulose derivatives. While these substrates have been important in determining the role of substrate characteristics in hydrolysis, they have also raised new questions about the behavior of enzymes on heterogeneous substrates such as plant biomass and wood. The presence of other compositional constituents may influence the cellulolytic mechanism, and other "multifunctional" enzymes may be required to achieve total saccharification. The size and mode of action of hydrolytic enzymes influence their degradative capabilities, with most structural modifications occurring at the substrate surfaces. How these large enzymes can penetrate into highly ordered cellulose and disrupt its integrity remains a question. The concept of "amorphogenesis" and the existence of a C1 cellulase are still debated. The role of oxidoreductases such as cellobiose dehydrogenase in cellulose degradation is also under investigation. This paper does not attempt to directly answer these questions but indicates that many questions have been answeredThe ability of microbial enzyme systems to completely hydrolyze the structural polysaccharides of plant cell walls has been the focus of extensive research. While many enzymes have been identified and characterized, no single mechanism for total lignocellulosic saccharification has been established. The heterogeneous nature of lignocellulosic matrices makes it difficult to fully understand the interactions between enzyme complexes and these substrates. The efficacy of enzymatic complexes to hydrolyze these substrates is closely linked to the structural characteristics of the substrate and the modifications that occur during saccharification. This review aims to illustrate the potential enzymatic and structural limitations that influence the complete hydrolysis of lignocellulosic polysaccharides. Despite extensive research, our understanding of how enzymes completely hydrolyze lignocellulosic substrates remains incomplete. Substrate complexity and the need for multiple enzymes to effectively and completely hydrolyze these substrates have been well established. The repeating β-1–4 linking cellobiose unit is not indicative of the complex arrangement of the substrate at the fibril, fiber, and wood/pulp levels. Although tools like molecular biology and protein engineering have helped elucidate the role of some enzymes in the synergistic attack of lignocellulosic substrates, our understanding of basic mechanisms such as enzyme regulation, kinetics, and the extent of true synergism is still lacking. Research has focused on identifying the limiting factors in decreased hydrolysis rates, which are traditionally divided into two groups: those related to the structure of the substrate and those related to the mechanisms and interactions of the cellulase enzymes. Various model cellulose substrates have been used to study the mechanism of action and interaction of individual cellulase enzymes and the effect of substrate characteristics on the rate and efficiency of enzymatic hydrolysis. These include Avicel, solka floc, filter paper, cotton, valonia cellulose, phosphoric acid swollen cellulose, bacterial microcrystalline cellulose, and soluble cellulose derivatives. While these substrates have been important in determining the role of substrate characteristics in hydrolysis, they have also raised new questions about the behavior of enzymes on heterogeneous substrates such as plant biomass and wood. The presence of other compositional constituents may influence the cellulolytic mechanism, and other "multifunctional" enzymes may be required to achieve total saccharification. The size and mode of action of hydrolytic enzymes influence their degradative capabilities, with most structural modifications occurring at the substrate surfaces. How these large enzymes can penetrate into highly ordered cellulose and disrupt its integrity remains a question. The concept of "amorphogenesis" and the existence of a C1 cellulase are still debated. The role of oxidoreductases such as cellobiose dehydrogenase in cellulose degradation is also under investigation. This paper does not attempt to directly answer these questions but indicates that many questions have been answered