Despite the widespread acceptance of silicone hydrogel contact lenses, microbial keratitis remains the most significant complication associated with contact lens wear and Pseudomonas aeruginosa is still recognized as the leading causative organism. The purpose of this review is to summarize and update the current knowledge of the effects of lens type, oxygen transmissibility, wearing mode, and contact-lens care solutions on corneal epithelial biology and lens-induced P. aeruginosa binding from human and animal studies. The collective results of this work suggest that there is a net interactive effect on corneal epithelial cells among these risk factors. Significantly, hyper-oxygen-transmissible lenses in any wearing mode with non-preserved care solutions appear to offer the safest potential clinical choice for contact lens wear.