Mechanical properties of regenerated silk fibers are much lower than those of natural silk, due to inadequate understanding of the complex process of animal spun silk and inferior spinning processes and technologies available. In order to acquire regenerated silk fibers with good mechanical properties, the effects of pH, process parameters, metal ions, coagulation bath, post-treatment, solvents, and blending on the regenerated silk fibers are reviewed in this article. The solvents, pH, and metal ions affect the spinnability of the regenerated silk fibroin solution as well as the mechanical properties and biocompatibility of the spun fibers. Coagulation baths and post-treatment is crucial to the mechanical properties of the fibers. Microfluidics or similar methods for regenerated silk are highlighted in terms of mimicking the gradients of the silk gland. Additionally, we highlight microfluidics combined with electrospinning, which is a potential method to obtain regenerated silk fiber with good mechanical properties. A better combination of these factors may lead to the regenerated silk fibers with excellent mechanical properties, may be even beyond the capabilities of the natural silk fibers.