During the last 10 years, the emergence and spread of the most important and common resistant pathogens isolated from clinical infections led to the great release of new antibacterial agents. Many of new orally administered antibiotics introduced, such as newer fluoroquinolones or cephalosporins, showed a spectrum of activity and clinical efficacy for the most common clinical community infections. Therefore, therapeutic indication of a new cephalosporin is somewhat difficult to define, because the newer drugs must compete with improved properties over the previous ones. Therefore, choice of a first line antibiotic among apparently therapeutic equivalents could become questionable. The aim of this review was to compile the available data to offer help for a rational choice in confirmed infections of every particular patient condition and context based on microbiological activity, pharmacokinetic properties, clinical efficacy, safety and cost. Orally administered cephalosporins are beta-lactamic broad-spectrum antimicrobial agents that are often used empirically to treat community bacterial infections and also to treat culture-proven infections due to selected gram-positive and gram-negative microorganisms. Cephalosporins differ widely in their spectrum of activity, in vitro antimicrobial potency, microbial resistance, pharmaco-kinetic properties and cost. These differences result from modifications of the cephalosporin molecule. The substitutions on the R1, R2, R3 or R4 side chains results in changes in antimicrobial spectrum, potency, bioavailability, half-life and profile of toxicity. In general, the first-generation agents are more active against gram-positive organisms, more susceptible to B-lactamases of gram-negative producers, shorter serum half-life and lower cost than the other agents. The second-generation cephalosporins present enhanced spectrum of activity due to increased resistance to beta-lactamase enzymes and have longer serum half-life. The third-generation agents are the most active against Entero-bacteriaceae, possess a superior beta-lactamase stability against selected enzymes of multiple resistant bacteria, improved pharmacokinetic properties with extended plasma half-life, that permit once or twice daily administration and are the most expensive compared with the previous drugs. Among these new oral cephems, the addition of an ester group enhances the oral absorption from the gastrointestinal tract and provides better bioavailability as well as antimicrobial activity. The development of bacterial resistance has affected all steps of the cephalosporin mechanism of action. Expertise in the choice and use of the cephalosporins will remain a challenge for the physician, as additional investigational cephalosporins will continue to be developed and introduced into clinical practice in the near future.