Senecavirus A (SVA) is a nonenveloped, single-stranded, positive-sense RNA virus in the family Picornaviridae. It was first discovered as a cell culture contaminant in 2002 but had been identified in US swine samples dating back to the late 1980s. Since swine were presumed to be the natural host, pigs were experimentally inoculated, but did not develop any specific clinical disease. Prior to 2015, SVA was sporadically detected in US swine associated with various clinical histories. In 2015, cases of vesicular disease and increased neonatal mortality were observed in Brazil and subsequently in the US. SVA was consistently detected in affected animals. Although previous attempts to reproduce disease with SVA in the past were unsuccessful, experimental inoculation studies performed with contemporary isolates demonstrated SVA was a causative agent for vesicular disease in swine. SVA is now included in the differential list of etiologic agents that can cause vesicular disease in swine. This list includes foot-and-mouth disease virus (FMDV), which is a notifiable disease, so when vesicular lesions are observed in FMDV-free countries an investigation must be initiated to rule out FMDV. SVA has now been found across the Americas and Asia, and it appears the ecology of this virus has changed from sporadic infections to an endemic disease that does not induce severe clinical disease; but, its presence does have a significant impact since each case needs to be investigated as if it was a FMDV case. Thus, control and prevention measures are critical to reducing the spread of SVA in the global swine industry. Due to the difficulty of reproducing clinical disease in past experimental challenges and the timing of SVA outbreaks in the field with stressful situations, there was speculation that stress may be a factor in the development of vesicular lesions. To study the impact of stress, an immunosuppressive dexamethasone regime prior to SVA inoculation was administered. Clinical presentation and infection dynamics were similar in pigs treated with dexamethasone and those not treated prior to challenge. Another hypothesis for the lack of lesions in early experimental challenges was older isolates were less pathogenic than contemporary isolates. Vesicular lesion development and viral shedding in swine were compared between three SVA strains isolated prior to the 2015 outbreak and three strains isolated during 2015. The majority of animals in all groups developed vesicular lesions, and serum had cross neutralizing titers against all viruses. Sequencing and analysis of isolates used in the study found amino acid differences between the isolates in prominent loop structures of the capsid that may be involved with virus receptor binding and host immune response. Due to the clinical similarities between SVA and FMDV, control and prevention of SVA infections are a priority. Understanding the minimum infectious dose (MID) of SVA could provide insights into the infectivity of virus found in the environment and how the virus is spread. Finishing pigs and neonates were used to determine the MID of a 2011 SVA isolate using intranasal and oral challenge routes respectively. In this study, finishing pigs had a MID of 103.1 TCID50/mL and neonates 102.5 TCID50/mL. Although there were differences in infectious dose, fewer dilutions were tested in finishing pigs, which may provide a less precise estimate compared to the neonates. Another control measure for SVA could be vaccination. An inactivated vaccine was tested in weaned pigs and mature sows. The vaccine prevented the development of clinical signs and viremia as well as reduced rectal shedding in pigs. In addition, piglets suckling immunized dams had sterilizing immunity against SVA challenge. Overall, a better understanding of the pathogenesis of SVA in swine can help improve control and prevention measures to reduce the burden of SVA infection on the swine industry.