Porphyrins readily undergo S(N)Ar reactions with organolithium reagents, preferentially at the meso-positions. The reaction is highly versatile as it is accomplished with both metal complexes and free-base porphyrins in good yields and high regioselectivity. It can be used in sequence for the introduction of up to four different meso-substituents and is the first general method for the direct introduction of functional groups into unactivated porphyrins, including porphine. Depending on the porphyrin, the structure of the anionic intermediate, or the reaction conditions, this method also allows trapping of the intermediary anion with electrophiles, transformation into meso-meso-linked bisporphyrins, synthesis of phlorins or porphodimethenes, and beta-addition to yield hydroporphyrins.