The squamous ruminal epithelium (RE) is crucial for the performance of dairy cows because it is the main site for absorption of key nutrients (e.g., short-chain fatty acids, SCFA) and electrolytes (e.g., Na⁺ and Mg²⁺). The absorptive function has to be highly selective to prevent simultaneous entry of microbes and toxins from the ruminal content into the blood. As such, absorption is primarily via the transcellular route; whereas, the paracellular pathway is tightly sealed. The latter is accomplished by a network of tight junction (TJ) proteins (claudin-1, claudin-4, and occludin) and TJ-associated proteins (ZO-1); the network being most intense in the stratum granulosum where the decisive permeation barrier is located. When microbial fermentation activity is high, the integrity of absorbing cells and their connecting TJ is often challenged by acidity, high osmolarity, toxins, and by immune mediators released during inflammation of the RE. The epithelial damage induced by acidity has been studied most frequently. In contrast to the transient opening of the paracellular space induced by high luminal osmolarity, acidity-induced opening of the RE barrier is not immediately reversible and it even aggravates upon return to physiological pH values. A recent key finding has been that the RE can withstand low luminal pH values rather well in the absence of elevated concentrations of SCFA. It is essentially the combination of luminal acidity and high luminal SCFA concentration that determines the degree of RE damage during an acidotic incidence, with SCFA dose being more relevant than SCFA species. The initial insults set by luminal acidity and the increasing concentrations of microbe-derived toxins such as lipopolysaccharide during acidosis are among the key factors that trigger ruminal and systemic inflammation. Recent studies suggest that thiamine can ameliorate the local inflammation. Butyrate has also been claimed to reduce inflammation in recent studies; however, other studies support promotion of parakeratosis and epithelial injury by butyrate. Further research is needed to enhance the understanding of the various factors that make the barrier tight during epithelial adaptation to changing diets.