Cation-exchange membranes modified with polyelectrolyte multilayers (PEMs) could provide a platform for lithium purification based on the large hydrated radius and hydration energy of lithium relative to the corresponding values for other alkali metal ions. The PEMs give rise to Li+ selectivity, and the cation-exchange membrane allows separation through either Donnan dialysis (DD) or electrodialysis. Alternating adsorption of protonated poly(allylamine hydrochloride) (PAH) and poly(4-styrenesulfonate) (PSS) on Nafion 115 membranes increases the K+/Li+ DD selectivity and with source phases containing 0.01 M HNO3, the K+/Li+ selectivity reaches ~60. However, more recent studies suggest this may depend on the batch of cation-exchange membranes. Ellipsometric studies show increased PEM swelling at low pH, which may open cation-exchange sites that preferentially bind K+ to enable highly selective transport. Subsequent studies modified the interior of porous membrane with PEMs to allow attachment of small-molecule drugs and identification of their protein targets. A model system of carbonic anhydrase II (CAII) binding to immobilized 4-(2-aminoethyl)benzenesulfonamide (AEBSA) demonstrates the efficiency and selectivity of affinity capture in modified membranes. Selective elution of captured protein, tryptic digestion, tandem mass spectrometry analysis, and label-free quantification (LFQ) identify CAII as the dominant AEBSA target in diluted serum or cell lysate Global proteomics shows that the spiked CAII is the only protein with a log2 ratio (sample/control intensity) consistently >2, and the detection limit for CAII identification is 0.004 wt% of the total protein in 1:4 diluted human serum or 0.024 wt% of the total protein from breast cancer cell lysates. The same approach also identifies native CAII in human kidney cell lysate as an AEBSA target.Comparison of affinity capture using membranes, Affi-Gel 10 resin or M-270 Dynabeads derivatized with AEBSA suggests that only membranes allow identification of low-abundance CAII as a target.