The skin is colonized by a diverse collection of microorganisms which, for the most part, peacefully coexist with their hosts. Skin and soft tissue infections (SSTIs) encompass a variety of conditions; in immunocompromised hosts, SSTIs can be caused by diverse microorganisms-most commonly bacteria, but also fungi, viruses, mycobacteria, and protozoa. The diagnosis of SSTIs is difficult because they may commonly masquerade as other clinical syndromes or can be a manifestation of systemic disease. In immunocompromised hosts, SSTI poses a major diagnostic challenge, and clinical dermatological assessment should be initially performed; to better identify the pathogen and to lead to appropriate treatment, etiology should include cultures of lesions and blood, biopsy with histology, specific microbiological analysis with special stains, molecular techniques, and antigen-detection methodologies. Here, we reviewed the epidemiology, pathophysiology, clinical presentation, and diagnostic techniques, including molecular biological techniques, used for SSTIs, with a focus on the immunocompromised host, such as patients with cellular immunodeficiency, HIV, and diabetic foot infection.