During the past two decades, there has been an explosion of new knowledge and techniques in the field of recombinant protein expression. However, over-expression of "difficult to express proteins" with therapeutic importance continues to be a challenging task for successful commercialization of these proteins. With the emergence of the bio-similar market, enhancing the efficiencies of the production process has become a critical factor in the commercial viability of novel products. Despite the availability of numerous technological advancements, recombinant protein expression in Escherichia coli remains difficult. Therefore, addressing upstream bottlenecks in combination with genetically modified expression hosts could be a viable strategy to enhance production. Problems like poor expression, plasmid instability, protein aggregation, protein degradation, and metabolic stress associated with recombinant protein production need special consideration during bioprocess development at bioreactor level. However, a comprehensive universal strategy for attaining efficient expression in E. coli seems unrealistic and must be resolved empirically. In this review, we have discussed some common problems and their apparent solutions for plasmids based recombinant gene expression in E. coli. (C) 2017 Elsevier Ltd. All rights reserved.