Gas separation membranes are expected to play a significant role in green house reduction, renewable energy production, and energy savings for separations. However, newly developed membrane materials are constrained by the trade-off between selectivity and permeability and existing body of literature lacks the clear guidance on directions for the investigation. In this paper, we first systematically reviewed the effects of mixed gases and contaminants on membrane selectivities from gas transport mechanism. We then examined cascade membrane process design to achieve the desired product recovery and purity, utilizing two types of membranes and utilizing pressure ratio as the guidance to design the stages. From these examinations, we concluded that high membrane selectivity is critically needed, while high membrane permeability has limited impact for practical applications. Process design and economics for biogas purification was utilized as an example to demonstrate the need for high selectivity membranes. We further identified some gas separation applications that are critically in need of high membrane selectivities, such as CO2 capture from flue gases, and highlighted recent progress in membrane materials with high gas selectivities for these applications.