Cell-penetrating poly(disulfide)s (CPDs) have been introduced recently to explore new ways to enter into cells. In this report, we disclose a general method to covalently modify the sidechains of CPDs. Compatibility of copper-catalyzed alkyne-azide cycloaddition (CuAAC) with the addition of either strained cyclic disulfides of varied ring tension or increasing numbers of guanidinium and phosphonium cations is demonstrated. Reloading CPDs with disulfide ring tension results in an at least 20-fold increase in activity with preserved sensitivity toward inhibition with the Ellman's reagent. The cumulation of permanent positive charges by sidechain engineering affords Ellman-insensitive CPDs with similarly increased activity. Co-localization experiments indicate that the CPDs reach endosomes, cytosol and nucleus, depending on their nature and their concentration. Supported by pertinent controls, these trends confirm that CPDs operate with combination of counterion- and thiol-mediated uptake, and that the balance between the two can be rationally controlled. For the most active CPDs, uptake can be observed at substrate (fluorophore) concentrations as low as 5 nm.