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Clostridium septicum is a Gram-positive anaerobic bacillus that causes serious, life-threatening infections, including aggressive septicemia and myonecrosis. Clostridial myonecrosis can be broadly classified into two defined clinical presentations: traumatic and spontaneous. Clostridium perfringens is the most common cause of traumatic myonecrosis, while C. septicum is the most common etiological agent of spontaneous myonecrosis. Although rarely clinically encountered, C. septicum infections are often fatal. Disease is thought to be initiated by the transfer of C. septicum from the gut to the bloodstream through gastric epithelial lesions. C. septicum infections are strongly associated with colonic and hematological malignancy, which can cause or facilitate the formation of lesions. Subsequent bacteremia allows the establishment of C. septicum at distal anatomical sites, which can manifest as spontaneous myonecrosis, or necrotizing enterocolitis in neutropenic patients. Here, we present a summary of the current knowledge related to the pathogen, highlighting clinical manifestations, molecular pathogenesis, and the diagnostic significance of C. septicum in the clinical setting.