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The skin can serve as an interstitial Na⁺ reservoir. Local tissue Na⁺ accumulation increases with age, inflammation and infection. This increased local Na⁺ availability favors pro-inflammatory immune cell function and dampens their anti-inflammatory capacity. In this review, we summarize available data on how NaCl affects various immune cells. We particularly focus on how salt promotes pro-inflammatory macrophage and T cell function and simultaneously curtails their regulatory and anti-inflammatory potential. Overall, these findings demonstrate that local Na⁺ availability is a promising novel regulator of immunity. Hence, the modulation of tissue Na⁺ levels bears broad therapeutic potential: increasing local Na⁺ availability may help in treating infections, while lowering tissue Na⁺ levels may be used to treat, for example, autoimmune and cardiovascular diseases.