Methods used in the treatment of acute and chronic wounds undergo constant evolution, reevaluation, and innovation. While negative-pressure wound therapy (NPWT) is an established treatment modality, the combination of NPWT and instillation of normal saline as well as solutions with active antiseptic components for topical treatment of the wound bed represents a novel approach. The well-known effects of NPWT may thus be combined with those of local antisepsis. They include a decrease in wound area, induction of granulation tissue, and reduction in bacterial colonization. To date, studies have focused on NPWT with instillation for orthopedic/surgical indications, whereas clinical data in dermatosurgery is limited to case reports or small case series. There are as yet no randomized prospective studies investigating NPWT with instillation in the treatment of skin disorders. The goal of this review is to present the method of NPWT with instillation, to highlight its mode of action as well as possible complications and contraindications, and to review the recent literature. In summary, there is increasing evidence that both simple and complicated wounds may be effectively treated with NPWT with instillation, resulting in markedly accelerated tissue granulation and thus earlier defect closure.