Digitalis compounds are used in the treatment of congestive heart failure as positive inotropic agents; their action is mainly due to the inhibition of the Na(+),K(+)-ATPase. A well-known drawback is their arrhythmogenic potential together with a low therapeutic index. Digitalis compounds are characterized by a cis/trans/cis steroidal skeleton with an alpha,beta-unsaturated lactone (gamma-butyrolactone) in the 17beta-position, a 14beta-hydroxy group and a 3beta-hydroxy group, the latter usually linked to one or more sugar rings. The first three moieties are considered essential for inotropic activity, while the glycosides are responsible for the pharmacokinetics of the compounds. This review briefly reports on some of the replacements for the unsaturated gamma-butyrolactone moiety and then summarizes the work at Prassis that led to the discovery of the O-aminoalkyloxime group as a very powerful substitute. We also report on the development of new steroidal compounds which act as digitalis-like inhibitors of the Na(+),K(+)-ATPase, without any of the chemical features that are peculiar to naturally occurring digitalis glycosides.