Clindamycin continues to be an important agent for the management of infections due to gram-positive cocci and anaerobes. Such pathogens are frequently important in skin, soft tissue, and deep infections of the foot. Erythromycin has an impressive safety record and has retained its activity against many organisms, including several that play a role in infections of the foot. Clindamycin and erythromycin are frequently used as alternatives to the penicillins and cephalosporins. Newer macrolides, in comparison to erythromycin, have similar antimicrobial spectra of activity, improved pharmacokinetic parameters, and better tissue penetration. As new microorganisms emerge as clinical problems, newer macrolides may play a therapeutic role.