Quantitative structure-activity relationships (QSARs) of different cardiotonic agents are presented. A critical analysis of all QSARs provides a very vivid picture of the mechanisms of varying cardiotonic agents. The cardiotonics can be broadly put into 2 categories: cardiac glycosides and nonglycoside cardiotonics, which include phosphodiesterase of type III (PDE III) inhibitors, sympathomimetic (adrenergic) stimulants, A1-selective adenosine antagonists, Ca2+ channel activators and vasopressin antagonists. For cardiac glycosides, QSARs reveal that the position of carbonyl oxygen in their lactone moiety and shifting of the lactone ring from its original position or its replacement by another group would be crucial for their activity. The carbonyl group or its isostere like CN is indicated to be the sole binding entity and the hydrogen bonding through this group is considered to be the most likely binding force. For nonglycoside cardiotonics that include PDE III inhibitors and A1-selective antagonists, a five-point model has been established for their activity, the salient features of which are: (1) the presence of a strong dipole, (2) an adjacent acidic proton, (3) a methyl-sized lipophilic space, (4) a relatively flat overall topography and (5) a basic or hydrogen-bond acceptor site opposite to the dipole. For Ca2+ channel activators, the importance of steric, electrostatic, lipophilic and hydrogen-bonding properties of molecules is indicated, while for vasopressin antagonists the lipophilic and electronic properties are suggested to be the most important.