The bacterial cell envelope, consisting primarily of the cell membrane and the cell wall, is the most important physical and structural barrier. The cell wall provides the cell with structural strength and protects it from lysis due to the high turgor. The cytoplasmic membrane functions as a molecular sieve, controlling the transport of specific proteins, and nutrients. Because many aspects of the cell envelope are specific to bacteria, it is also a prime target for antibiotics. To date, at least 17 classes of antibiotics are available for treatment; however, to each class bacteria have developed resistance. This selective pressure within bacteria not only originates from the widespread use of antibiotics, it is also inherent in the natural environment of many soil dwelling prokaryotes which evolved to produce antibiotics as signaling molecules or for nutrient competition. Here, we have investigated the response of the Gram-positive model bacterium Bacillus subtilis to commonly used cell envelope active antibiotics. By combining global analytical techniques, including microarray analyses, proteomic studies, transposon mutagenesis, whole genome sequencing, and fluorescence and electron microscopy, we obtained a clearer picture of the response of B. subtilis to daptomycin, moenomycin, ramoplanin, fosfomycin, and duramycin. In addition, we discuss mechanisms of resistance to these antibiotics.